**3. Scientific rationale for the limited translational success: What have we learned?**

Based on the records published by National Institute of Neurological Disorders and Stroke (NINDS), a main source of DPN research, about 16,488 projects were funded at the expense of over \$8 billion for the fiscal years of 2008 through 2012. Of these projects, an estimated 72,200 animals were used annually to understand basic physiology and disease pathology as well as to evaluate potential drugs [255]. As discussed above, however, the usefulness of these pharmaceutical agents developed through such a pipeline in preventing or reducing neuronal damage has been equivocal and usually halted at human trials due to toxicity, lack of efficacy or both (Figure 1). Clearly, the pharmacological translation from our decades of experimental modeling to clinical practice with regard to DPN has thus far not even close to satisfactory. Undoubtedly, the flawed design of some clinical trials has led to the inadequate evaluation of certain candidate compounds and for a thorough discussion on this specific topic the readers are referred elsewhere [256]. In this section, we focus on discussing some of the fundamental species differences that render a direct translation unrealistic.

### **3.1. Failure to predict toxic effects**

of other reactive oxygen (ROS) and nitrogen species (RNS) such as hydrogen peroxide (H2O2), hydroxyl radicals (OH•) and peroxynitrite (NO•). Other hyperglycemia-initiated events such as AGE formation and NGF deficiency have also been suggested to fuel the ROS generation in various compartments. These highly reactive free radicals can non-specifically oxidize and nitrosylate cellular/extracellular biomolecules and undermine organellar function. Particular‐ ly, increased protein nitration, lipid peroxidation products and mitochondria dysfunction are predominant phenomena in DRGs and sciatic nerves in diabetic animals [240-242]. Compared to the clear evidence of oxidative damage in experimental DPN, expression of the correspond‐ ent biomarkers indicating oxidative stress in human tissues is rather vague [239, 243]. Some studies even suggested a reduced free radical reaction in diabetic patients versus normal control [244, 245]. Further, despite a strong rationale and the promise of substantial neuro‐ protection by anti-oxidant treatments in rodent diabetics [246-249], this anti-oxidative ap‐ proach is not spared from the irreproducibility of the results obtained from basic research in

42 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

Among a number of anti-oxidants that corrected experimental DPN, α-lipoic acid (ALA) has gone the furthest into clinical use, while the others have proven largely ineffective [14, 250]. ALA or thioctic acid is naturally synthesized in mitochondria and has a powerful antioxidant capacity because of its dual ability to scavenge ROS/transition metals and regenerate other endogenous antioxidants. Approximately 7 double-masked multicenter RCTs, including the series of ALADIN, SYDNEY and NATHAN, testing the efficacy of ALA in treating sympto‐ matic DPN have been completed in Europe [251]. Of these, a general benefit on sensory symptoms and deficits was extrapolated by a meta-analysis incorporating 4 trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) that treated subjects with 600 mg/day ALA via intravenous infusion for 3 weeks [252]. However, there is an overall mixed bag of results and several therapeutically important indices including symptoms score, nerve conduction and QST were not consistently ameliorated in these studies [205, 252, 253]. Notably, some asserted improvement fell below the clinically meaningful threshold of 30% when adjusted to placebo control [254]. It is also discouraging that trials in which patients received oral dosing of ALA presented only marginal benefit; this significantly precludes the oral application of ALA. Although ALA has been marketed in Germany for treating DPN and is available as nutritional supplement in the US, current existing evidence suggests that ALA at best only retards the

**3. Scientific rationale for the limited translational success: What have we**

Based on the records published by National Institute of Neurological Disorders and Stroke (NINDS), a main source of DPN research, about 16,488 projects were funded at the expense of over \$8 billion for the fiscal years of 2008 through 2012. Of these projects, an estimated 72,200 animals were used annually to understand basic physiology and disease pathology as well as to evaluate potential drugs [255]. As discussed above, however, the usefulness of these pharmaceutical agents developed through such a pipeline in preventing or reducing neuronal

clinical practice.

neuropathic progression in diabetes.

**learned?**

Whereas a majority of the drugs investigated during preclinical testing executed experimen‐ tally desired endpoints without revealing significant toxicity, more than half that entered clinical evaluation for treating DPN were withdrawn as a consequence of moderate to severe adverse events even at a much lower dose. Generally, using other species as surrogates for human population inherently encumbers the accurate prediction of toxic reactions for several reasons.

First of all, it is easy to dismiss drug-induced non-specific effects in animals—especially for laboratory rodents who do not share the same size, anatomy and physical activity with humans. Events such as cardiac attack are often overlooked without a complex and careful examination. A case in point is the anti-diabetic drug Avandia for which the market approval has been a center of dispute. Avandia's active ingredient rosiglitazone promotes insulin sensitivity by activating peroxisome proliferator-activated receptors (PPARs) and was claimed by its maker GlaxoSmithKline to be safe in the preclinical report. Some even went further to advocate the favorable application of rosiglitazone to heart conditions based on its positive influence on cardiovascular biomarkers in rodent studies [257, 258]. Only after accumulating incidents of congestive heart failure among patients receiving Avandia was presented to the FDA, did it begin to spur wide concerns and active investigations of the serious cardiotoxicity by Avandia in humans and animals [259].

Second, some physiological and behavioral phenotypes observable in humans are impossible for animals to express. In this aspect, photosensitive skin rash and pain serve as two good examples of non-translatable side effects. Rodent skin differs from that of humans in that it has a thinner and hairier epidermis and distinct DNA repair abilities [260]. Therefore, most rodent stains used in diabetes modeling provide poor estimates for the probability of cutane‐ ous hypersensitivity reactions to pharmacological treatments [261]. Although skin engraft‐ ment onto nude mice has been attempted to circumvent this issue [260], mice with immunodeficiency do not constitute an appropriate background for studying diabetes. Another predicament is to assess pain in rodents. The reason for this is simple: these animals cannot tell us when, where or even whether they are experiencing pain, leaving us to read. Since there is not any specific type of behavior to which painful reaction can be unequivocally associated, this often leads to underestimation of painful side effects during preclinical drug screening (e.g. rhNGF).

The third problem is that animals and humans have different pharmacokinetic and toxicologi‐ cal responses. For instance, troglitazone (Rezulin), another anti-hyperglycemic PPAR agonist,

described earlier, sensory neuropathy in humans typically adopts a length-dependent, "stocking-glove" lossof sensationthat slowlyprogresses fromdistaltoproximal. Suchapattern was never functionally recapitulated in the commonly used type 1 and type 2 diabetic animal models, including STZ-injected rats, Zucker diabetic fatty (ZDF) rats and db/db mice. Besides the lack of anatomical resemblance, the changes in disease severity are often missing in these models. For example, although the majority of diabetic rodent models developed thermal hypoalgesia with long durations of diabetes as revealed by the sensory assay correspondent to that of QSTs in humans, there is no agreement between different studies in a consistent trend of progressive decline in thermal pain perception [270-272], a well-known phenomenon in patients. Alterations in thermal sensation in the tails of diabetic rodents varied upon studies and species used [273-275] and several groups have documented increased temperature perception after prolonged diabetes [276, 277], thus falsifying the relevance of tail flick test to human conditions. More importantly, foot ulcers that occur as a late complication to 15% of all individuals with diabetes [14] do not spontaneously develop in hyperglycemic rodents. Superimposed injury by experimental procedure in the foot pads of diabetic rats or mice may lend certain insight in the impaired wound healing in diabetes [278] but is not reflective of the chronic, accumulating pathological changes in diabetic feet of human counterparts. Another salientfeatureofhumanDPNthathasnotbeendescribedinanimals is thepredominant sensory and autonomic nerve damage versus minimal involvement of motor fibers [279]. This should elicit particular caution as the selective susceptibility is critical to our true understanding of the etiopathogenesisunderlyingdistal sensorimotorpolyneuropathy indiabetes.Inadditionto the lack of specificity, most animal models studied only cover a narrow spectrum of clinical DPN and have not successfully duplicated syndromes including proximal motor neuropathy and

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45

Morphologically, fiber atrophy and axonal loss exist in STZ-rats and other diabetic rodents but are much milder compared to the marked degeneration and loss of myelinated and unmyeli‐ nated nerves readily observed in human specimens [280]. Of significant note, rodents are notoriously resistant to developing some of the histological hallmarks seen in diabetic patients, such as segmental and paranodal demyelination [44]. There are sporadic reports of demyeli‐ nation in STZ and genetically diabetic Bio-Breeding (BB) rats after 8-12 months of diabetes [58, 281-283]. However, this is apparently related to a different microvascular pathology as morphometric analysis of sural and tibial vasa nervorum in these rats revealed dilated lumina, flattening of endothelial cells and microvessel walls [284], contrasting with the basement membrane thickening, endothelial hyperplagia and narrowing of endoneurial lumen in human diabetics [285, 286]. Similarly, the simultaneous presence of degenerating and regen‐ erating fibers that is characteristic of early DPN has not been clearly demonstrated in these animals [44]. Since such dynamic nerve degeneration/regeneration signifies an active state of nerve repair and is most likely to be amenable to therapeutic intervention, absence of this property makes rodent models a poor tool in both deciphering disease pathogenesis and designing treatment approaches. Given that our ability to devise a cure for human DPN depends ultimately on our successful understanding and reduction of its various functional and structural indexes, failure of most animal models to replicate these human neuropathol‐

ogies with high fidelity renders this task difficult at best.

focal lesions [279].

was withdrawn after inducing idiosyncratic liver failure in patients but a similar hepatotoxici‐ ty could not be reproduced in animal models [262, 263]. Even in organ systems that were previously defined as having an overall high rate of interspecies toxicity concordance, unanti‐ cipated drug toxicity can still occur. This was the case for trastuzumab (Herceptin), a human‐ izedmonoclonalantibodythattreatsadvancedbreastcarcinomabybindingandblockinghuman epidermal growth factor receptor 2 (HER2). Both preclinical and on-going toxicological studies in rhesus monkeys and rodents indicated no evidence of cardiac dysfunction [264]. However, trastuzumab administration to patients during clinical trials caused frequent and severe cardiomyopathy [265].Asdiscussedin apublishedscientificdocument of Herceptin toxicity by the European Medicines Agency, it is also unsuitable to assess the cytotoxicity of this antibody that specifically recognizes a single human protein in nonhuman species which have a distinct molecular and immunogenic environment [264]. In addition to the inaccuracies, disparities in pharmacokinetics underpin some of the extreme species differences. MPTP (1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity is a classic example. MPTP be‐ comespoisonoustodopaminergicneuronsoncemetabolizedtoMPP+bytheenzymemonoamine oxidase-B(MAO-B) andelicitspermanentParkinson-like symptoms inhumansubjects [266].In sharp contrast, MPTP is barely psychoactive in rats since they produce minimal MPP+ and only milddamage tomouse brainsdue tomuchfaster clearance ofMPP+ comparedtoprimates [267]. By the same token, 350 mg of aspirin can be eliminated by half from human circulation in about 3 hours but retained in feline plasma for 37.5 hours, which is essentially lethal to these animals [268]. The argument can be finally strengthened by the work of two independent groups, who compared bioavailability between primates, rodents and dogs for various drugs and both demonstrated that no correlation exists between animal and human data [269]. The matter of drug-induced non-specific effects and uniquely human phenotypes may theoretically be resolved via rigorous pathological evaluation and better experimental method. By compari‐ son, the pharmacokinetic and toxicological data highlights profound interspecies barriers and may not succumb to current technical manipulation. Considering some of the drugs were withdrawn when unexpected toxicological outcomes occur in only 1-2% of the population, relying on laboratory models to predict drug safety certainly puts us in a dilemma with very little medical and ethical risks from which our society can suffer (Figure 1).

#### **3.2. Failure to recapitulate human neuropathologies**

Genetic or chemical-induced diabetic rats or mice have been a major tool for preclinical pharmacological evaluation of potential DPN treatments. Yet, they do not faithfully repro‐ duce many neuropathological manifestations in human diabetics. The difficulty of such begins with the fact that it is not possible to obtain in rodents a qualitative and quantitative expres‐ sion of the clinical symptoms that are frequently presented in neuropathic diabetic patients, including spontaneous pain of different characteristics (e.g. prickling, tingling, burning, squeezing), paresthesia and numbness. As symptomatic changes constitute an important parameter of therapeutic outcome, this may well underlie the failure of some aforementioned drugs in clinical trials despite their good performance in experimental tests measuring behavioral responses of animals to external stimuli (Table 1). Development of nerve dysfunc‐ tion in diabetic rodents also does not follow the common natural history of human DPN. As described earlier, sensory neuropathy in humans typically adopts a length-dependent, "stocking-glove" lossof sensationthat slowlyprogresses fromdistaltoproximal. Suchapattern was never functionally recapitulated in the commonly used type 1 and type 2 diabetic animal models, including STZ-injected rats, Zucker diabetic fatty (ZDF) rats and db/db mice. Besides the lack of anatomical resemblance, the changes in disease severity are often missing in these models. For example, although the majority of diabetic rodent models developed thermal hypoalgesia with long durations of diabetes as revealed by the sensory assay correspondent to that of QSTs in humans, there is no agreement between different studies in a consistent trend of progressive decline in thermal pain perception [270-272], a well-known phenomenon in patients. Alterations in thermal sensation in the tails of diabetic rodents varied upon studies and species used [273-275] and several groups have documented increased temperature perception after prolonged diabetes [276, 277], thus falsifying the relevance of tail flick test to human conditions. More importantly, foot ulcers that occur as a late complication to 15% of all individuals with diabetes [14] do not spontaneously develop in hyperglycemic rodents. Superimposed injury by experimental procedure in the foot pads of diabetic rats or mice may lend certain insight in the impaired wound healing in diabetes [278] but is not reflective of the chronic, accumulating pathological changes in diabetic feet of human counterparts. Another salientfeatureofhumanDPNthathasnotbeendescribedinanimals is thepredominant sensory and autonomic nerve damage versus minimal involvement of motor fibers [279]. This should elicit particular caution as the selective susceptibility is critical to our true understanding of the etiopathogenesisunderlyingdistal sensorimotorpolyneuropathy indiabetes.Inadditionto the lack of specificity, most animal models studied only cover a narrow spectrum of clinical DPN and have not successfully duplicated syndromes including proximal motor neuropathy and focal lesions [279].

was withdrawn after inducing idiosyncratic liver failure in patients but a similar hepatotoxici‐ ty could not be reproduced in animal models [262, 263]. Even in organ systems that were previously defined as having an overall high rate of interspecies toxicity concordance, unanti‐ cipated drug toxicity can still occur. This was the case for trastuzumab (Herceptin), a human‐ izedmonoclonalantibodythattreatsadvancedbreastcarcinomabybindingandblockinghuman epidermal growth factor receptor 2 (HER2). Both preclinical and on-going toxicological studies in rhesus monkeys and rodents indicated no evidence of cardiac dysfunction [264]. However, trastuzumab administration to patients during clinical trials caused frequent and severe cardiomyopathy [265].Asdiscussedin apublishedscientificdocument of Herceptin toxicity by the European Medicines Agency, it is also unsuitable to assess the cytotoxicity of this antibody that specifically recognizes a single human protein in nonhuman species which have a distinct molecular and immunogenic environment [264]. In addition to the inaccuracies, disparities in pharmacokinetics underpin some of the extreme species differences. MPTP (1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity is a classic example. MPTP be‐ comespoisonoustodopaminergicneuronsoncemetabolizedtoMPP+bytheenzymemonoamine oxidase-B(MAO-B) andelicitspermanentParkinson-like symptoms inhumansubjects [266].In

44 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

sharp contrast, MPTP is barely psychoactive in rats since they produce minimal MPP+

little medical and ethical risks from which our society can suffer (Figure 1).

**3.2. Failure to recapitulate human neuropathologies**

milddamage tomouse brainsdue tomuchfaster clearance ofMPP+ comparedtoprimates [267]. By the same token, 350 mg of aspirin can be eliminated by half from human circulation in about 3 hours but retained in feline plasma for 37.5 hours, which is essentially lethal to these animals [268]. The argument can be finally strengthened by the work of two independent groups, who compared bioavailability between primates, rodents and dogs for various drugs and both demonstrated that no correlation exists between animal and human data [269]. The matter of drug-induced non-specific effects and uniquely human phenotypes may theoretically be resolved via rigorous pathological evaluation and better experimental method. By compari‐ son, the pharmacokinetic and toxicological data highlights profound interspecies barriers and may not succumb to current technical manipulation. Considering some of the drugs were withdrawn when unexpected toxicological outcomes occur in only 1-2% of the population, relying on laboratory models to predict drug safety certainly puts us in a dilemma with very

Genetic or chemical-induced diabetic rats or mice have been a major tool for preclinical pharmacological evaluation of potential DPN treatments. Yet, they do not faithfully repro‐ duce many neuropathological manifestations in human diabetics. The difficulty of such begins with the fact that it is not possible to obtain in rodents a qualitative and quantitative expres‐ sion of the clinical symptoms that are frequently presented in neuropathic diabetic patients, including spontaneous pain of different characteristics (e.g. prickling, tingling, burning, squeezing), paresthesia and numbness. As symptomatic changes constitute an important parameter of therapeutic outcome, this may well underlie the failure of some aforementioned drugs in clinical trials despite their good performance in experimental tests measuring behavioral responses of animals to external stimuli (Table 1). Development of nerve dysfunc‐ tion in diabetic rodents also does not follow the common natural history of human DPN. As

and only

Morphologically, fiber atrophy and axonal loss exist in STZ-rats and other diabetic rodents but are much milder compared to the marked degeneration and loss of myelinated and unmyeli‐ nated nerves readily observed in human specimens [280]. Of significant note, rodents are notoriously resistant to developing some of the histological hallmarks seen in diabetic patients, such as segmental and paranodal demyelination [44]. There are sporadic reports of demyeli‐ nation in STZ and genetically diabetic Bio-Breeding (BB) rats after 8-12 months of diabetes [58, 281-283]. However, this is apparently related to a different microvascular pathology as morphometric analysis of sural and tibial vasa nervorum in these rats revealed dilated lumina, flattening of endothelial cells and microvessel walls [284], contrasting with the basement membrane thickening, endothelial hyperplagia and narrowing of endoneurial lumen in human diabetics [285, 286]. Similarly, the simultaneous presence of degenerating and regen‐ erating fibers that is characteristic of early DPN has not been clearly demonstrated in these animals [44]. Since such dynamic nerve degeneration/regeneration signifies an active state of nerve repair and is most likely to be amenable to therapeutic intervention, absence of this property makes rodent models a poor tool in both deciphering disease pathogenesis and designing treatment approaches. Given that our ability to devise a cure for human DPN depends ultimately on our successful understanding and reduction of its various functional and structural indexes, failure of most animal models to replicate these human neuropathol‐ ogies with high fidelity renders this task difficult at best.


Abbreviations: NOD=non-obese diabetic, AR=aldose reductase

(to be inserted in page 15, the texts continues on page 16)

**3.3. Overrepresentation of pathogenetic pathways**

clinical trials.

STZ is a glucose analog of selective toxicity to pancreatic β-cells and induces insulin-deficiency and hyperglycemia mimicking that in human type 1 diabetes mellitus. Injection of this chemical provides a convenient and affordable tool in inducing robust hyperglycemia in animals with good control over disease onset and duration. Therefore, STZ-rats have been favored by researchers during preclinical drug assessments for diabetic complications [280]. However, STZ typically produces a rather immediate, severe hypoinsulinemia and elevation of blood glucose, whereas the development of hyperglycemia in most human conditions is slow and modest [287]. The contrariety manifests stably in the serum HbA1c levels. While the non-diabetic range (~4-5.6%) is similar, a single administration of STZ to Wistar rats can increase the HbA1c to above 12% in 4-5 weeks [288, 289], which indicates a very poor glucose control that is considered rare in the clinic setting with anti-diabetic care. In fact, less than 15% of patients may have an HbA1c level exceeding 9% by sample estimation [290]. Such extreme hyperglycemia in STZ-treated rats could give rise to exaggerated glucose accumulation and metabolic derangements that would not be commonly present in human diabetics. Indeed, the concentrations of sorbitol and fructose per unit weight of nerve tissue in STZ diabetic rats is consistently increased and dramatically higher in comparison with human diabetics, who on average also do not uniformly show upregulation of these glucose metabolites via polyol pathway [44, 55, 79]. Of interesting note, under normal physiological conditions the contents of nerve sorbitol in rodents are almost 10-fold higher than those in humans, suggesting some species difference in the relative involvement of AR in glucose metabolism during both normoand hyperglycemia. Observations of polyol pathway utilization in different species and cell types vary widely; the total glucose utilization through polyol pathway is one third in rabbit ocular lenses and only one tenth in human erythrocytes in response to high glucose stress [45, 291]. Consistent with an inverse association between increased polyol flux and electrophysio‐ logical dysfunction, diabetic rodents frequently exhibit 10 m/s or more reduction in NCV within the typical 6-20 week experimental duration [271, 292-294]. By contrast, the deteriora‐ tion of NCV in human patients gradually takes place and has an average loss of 0.5 m/s per year [1] (Table 1). It is also suspicious that the profound and precipitated NCV deceleration in STZ-rodents occur without apparent histopathological changes, which can be a prominent feature in diabetic neuropathic patients at early stage. Therefore, enhanced AR activity might contribute differently or less significantly to the pathogenesis of DPN in humans than rodents. This could explain why AR inhibitors, and by extension, many other pathogenetically targeted inhibitors afford potent neuroprotection in experimental studies but only marginal effects in

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Another criticism is that most STZ models were rendered diabetic at puberty since adminis‐ tering STZ to rodents after sexual maturation cannot always produce peripheral nerve abnormalities [280, 295]. Unlike matured nerves that displayed little change in response to diabetic insults, immature peripheral nerves readily manifest hyperglycemia-induced morphological and electrophysiological deficits within an even shorter duration [295]. However, such a phenotype bears little relevance to 90% of clinical conditions, in which

diabetes-induced nerve damage has an adult onset and slow time course.

Abbreviations: NOD=non-obese diabetic, AR=aldose reductase

**Table 1.** Comparison of DPN Characteristics between Humans and Frequently Used Laboratory Rodent Models

#### **3.3. Overrepresentation of pathogenetic pathways**

Abbreviations: NOD=non-obese diabetic, AR=aldose reductase

**Species/** 

**Models** 

**Humans** 

**Disease Genesis** multigenic monogenic

**Onset** chronic (years to decades) acute (3 days) moderate (2-5 months) unpredictable (4-30 weeks) mild (1-2 months) various, superimposed by

**Progression** slow, chronic (years to decades) Rapid (6-20 weeks) Slow (11-68 weeks)

**Glycemic Profile** moderate hyperglycemia severe hyperglycemia severe/fatal hyperglycemia, requires insulin for life preservation severe hyperglycemia normo- to mild hyper-glycemia moderate hyperglycemia

no clear definition/presentation of spontaneous pain or other symptoms;

thermal/mechanical hyperalgesia and tactile allodynia are often used as indication of increased pain perception however cannot be differentiated from increased sensory

**Induced Spontaneous Transgenic/** 

**Knockout mice STZ-rats/mice BB/Wor-rats NOD mice**

**ZDF rats ob/ob mice db/db mice** 

other diabetogenic

protocols

**Characteristics** 

Abbreviations: NOD=non-obese diabetic, AR=aldose reductase

**Symptoms** 

**Sensory Function** 

**Table 1.** Comparison of DPN Characteristics between Humans and Frequently Used Laboratory Rodent Models

varying degree and properties of pain,

paresthesia, numbness, insensitivity,

absent reflexes, muscle weakness

thermal hypoalgesia, decreased

vibration perception threshold, loss of

Achilles reflex

**Nerve Conduction** progressive decrease at a rate of 0.5m/s

per year

loss of unmyelinated and myelinated

fibers, evidence of axonal degeneration

distal axonotrophy, myelinated fiber atrophy, few

axonal loss, demyelination only after long-term

axonal atrophy and

degeneration not characterized

slight fiber atrophy and loss;

basement membrane thickening,

various

AR-overexpressing

mice exhibit

exaggerated increase

of polyol pathway

metabolites and

reduction of myoinositol amplifying specific

components,

applicable to rare

cases

narrowing of endoneuriallumina

sorbitol, fructose level normal or

moderately elevated;

myo-inositol level unchanged

hyperglycemia;

basement membrane flattening, widening of

microvascularlumina

and regeneration, segmental and

paranodal demyelination, distal

axonotrophy;

basement membrane thickening,

narrowing of endoneuriallumina

sorbitol, fructose content not altered or

slightly elevated, much lower

compared to rodents at both healthy

sorbitol, fructose level highly increased by diabetes;

myo-inositol level markedly reduced unclear

**Overall Limitation of the Model** phenotypic exaggeration and acceleration driven mostly by severe hyperglycemia representing early or prediabetesrather than overt diabetes

and diabetic states;

myo-inositol level unchanged

**Nerve Biochemistry** 

**Morphology** 

function

mechanical hyperalgesia,

thermal

thermal

thermal

hyperalgesia/

thermal/

thermal/

mechanical

thermal

hypoalgesia various

46 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

hypoalgesia

mechanical

hyperalgesia

>10m/s reduction within 6-20 weeks

hypoalgesia, tactile

allodynia

hyperalgesia

hyperalgesia/hypoalgesia,

mechanical/tactile allodynia

(to be inserted in page 15, the texts continues on page 16)

STZ is a glucose analog of selective toxicity to pancreatic β-cells and induces insulin-deficiency and hyperglycemia mimicking that in human type 1 diabetes mellitus. Injection of this chemical provides a convenient and affordable tool in inducing robust hyperglycemia in animals with good control over disease onset and duration. Therefore, STZ-rats have been favored by researchers during preclinical drug assessments for diabetic complications [280]. However, STZ typically produces a rather immediate, severe hypoinsulinemia and elevation of blood glucose, whereas the development of hyperglycemia in most human conditions is slow and modest [287]. The contrariety manifests stably in the serum HbA1c levels. While the non-diabetic range (~4-5.6%) is similar, a single administration of STZ to Wistar rats can increase the HbA1c to above 12% in 4-5 weeks [288, 289], which indicates a very poor glucose control that is considered rare in the clinic setting with anti-diabetic care. In fact, less than 15% of patients may have an HbA1c level exceeding 9% by sample estimation [290]. Such extreme hyperglycemia in STZ-treated rats could give rise to exaggerated glucose accumulation and metabolic derangements that would not be commonly present in human diabetics. Indeed, the concentrations of sorbitol and fructose per unit weight of nerve tissue in STZ diabetic rats is consistently increased and dramatically higher in comparison with human diabetics, who on average also do not uniformly show upregulation of these glucose metabolites via polyol pathway [44, 55, 79]. Of interesting note, under normal physiological conditions the contents of nerve sorbitol in rodents are almost 10-fold higher than those in humans, suggesting some species difference in the relative involvement of AR in glucose metabolism during both normoand hyperglycemia. Observations of polyol pathway utilization in different species and cell types vary widely; the total glucose utilization through polyol pathway is one third in rabbit ocular lenses and only one tenth in human erythrocytes in response to high glucose stress [45, 291]. Consistent with an inverse association between increased polyol flux and electrophysio‐ logical dysfunction, diabetic rodents frequently exhibit 10 m/s or more reduction in NCV within the typical 6-20 week experimental duration [271, 292-294]. By contrast, the deteriora‐ tion of NCV in human patients gradually takes place and has an average loss of 0.5 m/s per year [1] (Table 1). It is also suspicious that the profound and precipitated NCV deceleration in STZ-rodents occur without apparent histopathological changes, which can be a prominent feature in diabetic neuropathic patients at early stage. Therefore, enhanced AR activity might contribute differently or less significantly to the pathogenesis of DPN in humans than rodents. This could explain why AR inhibitors, and by extension, many other pathogenetically targeted inhibitors afford potent neuroprotection in experimental studies but only marginal effects in clinical trials.

Another criticism is that most STZ models were rendered diabetic at puberty since adminis‐ tering STZ to rodents after sexual maturation cannot always produce peripheral nerve abnormalities [280, 295]. Unlike matured nerves that displayed little change in response to diabetic insults, immature peripheral nerves readily manifest hyperglycemia-induced morphological and electrophysiological deficits within an even shorter duration [295]. However, such a phenotype bears little relevance to 90% of clinical conditions, in which diabetes-induced nerve damage has an adult onset and slow time course.

between humans and rodents, in terms of both extent and isoform specificity. The first is evident from the differential level of MAO-B expression in humans and rats which resulted in distinct susceptibility of these two species to MPTP-induced neurotoxicity [266]. The second category involves protein families comprising multiple isoforms owing to different promoter usage and alternative gene splicing. For instance, the enzyme PKC has at least 12 different subtypes, of which, PKC-α is predominantly expressed in human hearts and PKC-ε in rodents [298]. Since activation of PKC-α and PKC-ε are differentially regulated, species-specific PKC inhibitors will need to be developed in order to efficiently block the pathogenic action of this kinase in cardiomyopathy, especially when a non-selective inhibition of PKC function is unwanted or even detrimental. Given that the efficacy of ruboxistaurin in treating DPN was also based on data from rat diabetic models [150, 151], it is imperative to speculate that the unsatisfactory results of ruboxistaurin in patients is due at least in part to a relatively less important role of PKC-β in the pathological development of diabetic human nerves. The last type of molecular difference is that the components along a particular signaling axis may be preferentially vulnerable to pathological alteration in different species. This possibility has been largely ignored but could underpin a major limitation in current translational research. One typical example is that much has been learned regarding the anti-hyperphagic effects of leptin from ob/ob mice, which also led to the exciting finding that administration of this hormone can successfully suppress weight gain [299]. Nonetheless, this offered little treatment benefit for the majority of obese people (99.95%) who have impaired signaling downstream of leptin instead of leptin deficiency as observed in ob/ob mice [300]. Some may argue that these issues can be overcome by creating genetically engineered or "humanized" mice in which a mouse gene is substituted by the human version. However, transgenic or knockout mice can be afflicted with developmental deficits and alterations which are inappropriate for modeling a chronic disease that appears in the later life time, such as type 2 diabetes and its complications. Moreover, we do not know whether a genetically introduced human protein—if it is different enough from the murine orthologue that a transgene is necessary—faithfully maintains the

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same expression and interaction properties in mouse system as it would in humans.

Ultimately, a fundamental problem associated with resorting to rodents in DPN research is to study a human disorder that takes decades to develop and progress in organisms with a maximum lifespan of 2-3 years. The longest duration of experimental diabetes in a rodent model was documented by Ras *et al.,* who observed leptin-deficient db/db mice for 17 months and reported only mild pathological changes in the peripheral nerve fibers [301]. It is thus fair to say that a full clinical spectrum of the maturity-onset DPN likely requires a length of time exceeding the longevity of rodents to present and diabetic rodent models at best only help illustrate the very early aspects of the entire disease syndrome. Since none of the early pathogenetic pathways revealed in diabetic rodents will contribute to DPN in a quantitatively and temporally uniform fashion throughout the prolonged natural history of this disease, it is not surprising that a handful of inhibitors developed against these processes have not benefited patients with relatively long-standing neuropathy. As a matter of fact, any agents targeting single biochemical insults would be too little too late to treat a chronic neurological disorder with established nerve damage and pathogenetic heterogeneity (Figure 2). In DPN, such heterogeneity is the consequence of a complex interplay between genetic predisposition,

#### **3.4. Other physical and environmental factors**

Humans certainly share considerable biological similarities with other mammals. In the nervous system, these include some of the nociceptive responses and higher cognitive activities. At the same time, no one would suggest that humans and animals are the same they obviously differ in many physiological and behavioral aspects. The question is: can we obtain effective therapeutic applicability after evolution has well separated our species from others? In order to answer this, it is necessary to carefully examine these differences and their impacts on the pharmacokinetic and pharmacological extrapolation. As delineating every single molecular, cellular and phenotypic difference is a laborious task, we will highlight only those relevant to our discussion of DPN. When comparing humans with the conventionally used experimental animals, namely rats and mice, the most conspicuous difference is ana‐ tomical. With particular respect to neuroanatomy, a peripheral axon in humans can reach as long as one meter [296] whereas the maximal length of the axons innervating the hind limb is five centimeters in mice and twelve centimeters in rats. This short length makes it impossible to study in rodents the prominent length dependency and dying-back feature of peripheral nerve dysfunction that characterizes human DPN. Even if size were an issue and macrostructure appears similar, there might still be striking differences in the micro-structure within the tissue or organ. This is the case for insulin-secreting islets. For decades the cytoarchitecture of human islets was assumed to be just like those in rodents with a clear anatomical subdivision of β-cells and other cell types. By using confocal microscopy and multi-fluorescent labeling, it was finally uncovered that human islets have not only a substantially lower percentage of βcell population, but also a mixed—rather than compartmentalized—organization of the different cell types [297]. This cellular arrangement was demonstrated to directly alter the functional performance of human islets as opposed to rodent islets. Although it is not known whether such profound disparities in cell composition and association also exist in the PNS, it might as well be anticipated considering the many sophisticated sensory and motor activities that are unique to humans.

Considerable species difference also manifest at a molecular level. The chemical structure and signaling profile of a molecule may not always be conserved throughout the evolution. Such difference, although small, can account for a significant translational limitation for pharma‐ cological treatments targeted at a specific biomolecule. A good explanation is the case of trastuzumab. As mentioned earlier, trastuzumab was specifically designed to immunoantagonize HER2, thereby inhibiting cancer cell growth. However, this drug could not be adequately assessed in rodents or primates because of the inability of this human proteintargeting antibody to recognize the HER2 homologues expressed in these nonhuman species [264]. Despite the successful employment of nude mice for the preclinical evaluation of trastuzumab, a comprehensive pharmacological and pharmacokinetic profile was not ob‐ tained for this humanized antibody and it resulted in unpredicted toxicity in patients. While the molecular difference might not be as serious of a problem for rhNGF and rhVEGF, critical retrospective examination into this aspect may lend some insight into the failure of these gene therapies in DPN trials. At least 80% of human genes have a counterpart in the mouse and rat genome. However, temporal and spatial expression of these genes can vary remarkably between humans and rodents, in terms of both extent and isoform specificity. The first is evident from the differential level of MAO-B expression in humans and rats which resulted in distinct susceptibility of these two species to MPTP-induced neurotoxicity [266]. The second category involves protein families comprising multiple isoforms owing to different promoter usage and alternative gene splicing. For instance, the enzyme PKC has at least 12 different subtypes, of which, PKC-α is predominantly expressed in human hearts and PKC-ε in rodents [298]. Since activation of PKC-α and PKC-ε are differentially regulated, species-specific PKC inhibitors will need to be developed in order to efficiently block the pathogenic action of this kinase in cardiomyopathy, especially when a non-selective inhibition of PKC function is unwanted or even detrimental. Given that the efficacy of ruboxistaurin in treating DPN was also based on data from rat diabetic models [150, 151], it is imperative to speculate that the unsatisfactory results of ruboxistaurin in patients is due at least in part to a relatively less important role of PKC-β in the pathological development of diabetic human nerves. The last type of molecular difference is that the components along a particular signaling axis may be preferentially vulnerable to pathological alteration in different species. This possibility has been largely ignored but could underpin a major limitation in current translational research. One typical example is that much has been learned regarding the anti-hyperphagic effects of leptin from ob/ob mice, which also led to the exciting finding that administration of this hormone can successfully suppress weight gain [299]. Nonetheless, this offered little treatment benefit for the majority of obese people (99.95%) who have impaired signaling downstream of leptin instead of leptin deficiency as observed in ob/ob mice [300]. Some may argue that these issues can be overcome by creating genetically engineered or "humanized" mice in which a mouse gene is substituted by the human version. However, transgenic or knockout mice can be afflicted with developmental deficits and alterations which are inappropriate for modeling a chronic disease that appears in the later life time, such as type 2 diabetes and its complications. Moreover, we do not know whether a genetically introduced human protein—if it is different enough from the murine orthologue that a transgene is necessary—faithfully maintains the same expression and interaction properties in mouse system as it would in humans.

**3.4. Other physical and environmental factors**

that are unique to humans.

Humans certainly share considerable biological similarities with other mammals. In the nervous system, these include some of the nociceptive responses and higher cognitive activities. At the same time, no one would suggest that humans and animals are the same they obviously differ in many physiological and behavioral aspects. The question is: can we obtain effective therapeutic applicability after evolution has well separated our species from others? In order to answer this, it is necessary to carefully examine these differences and their impacts on the pharmacokinetic and pharmacological extrapolation. As delineating every single molecular, cellular and phenotypic difference is a laborious task, we will highlight only those relevant to our discussion of DPN. When comparing humans with the conventionally used experimental animals, namely rats and mice, the most conspicuous difference is ana‐ tomical. With particular respect to neuroanatomy, a peripheral axon in humans can reach as long as one meter [296] whereas the maximal length of the axons innervating the hind limb is five centimeters in mice and twelve centimeters in rats. This short length makes it impossible to study in rodents the prominent length dependency and dying-back feature of peripheral nerve dysfunction that characterizes human DPN. Even if size were an issue and macrostructure appears similar, there might still be striking differences in the micro-structure within the tissue or organ. This is the case for insulin-secreting islets. For decades the cytoarchitecture of human islets was assumed to be just like those in rodents with a clear anatomical subdivision of β-cells and other cell types. By using confocal microscopy and multi-fluorescent labeling, it was finally uncovered that human islets have not only a substantially lower percentage of βcell population, but also a mixed—rather than compartmentalized—organization of the different cell types [297]. This cellular arrangement was demonstrated to directly alter the functional performance of human islets as opposed to rodent islets. Although it is not known whether such profound disparities in cell composition and association also exist in the PNS, it might as well be anticipated considering the many sophisticated sensory and motor activities

48 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

Considerable species difference also manifest at a molecular level. The chemical structure and signaling profile of a molecule may not always be conserved throughout the evolution. Such difference, although small, can account for a significant translational limitation for pharma‐ cological treatments targeted at a specific biomolecule. A good explanation is the case of trastuzumab. As mentioned earlier, trastuzumab was specifically designed to immunoantagonize HER2, thereby inhibiting cancer cell growth. However, this drug could not be adequately assessed in rodents or primates because of the inability of this human proteintargeting antibody to recognize the HER2 homologues expressed in these nonhuman species [264]. Despite the successful employment of nude mice for the preclinical evaluation of trastuzumab, a comprehensive pharmacological and pharmacokinetic profile was not ob‐ tained for this humanized antibody and it resulted in unpredicted toxicity in patients. While the molecular difference might not be as serious of a problem for rhNGF and rhVEGF, critical retrospective examination into this aspect may lend some insight into the failure of these gene therapies in DPN trials. At least 80% of human genes have a counterpart in the mouse and rat genome. However, temporal and spatial expression of these genes can vary remarkably

Ultimately, a fundamental problem associated with resorting to rodents in DPN research is to study a human disorder that takes decades to develop and progress in organisms with a maximum lifespan of 2-3 years. The longest duration of experimental diabetes in a rodent model was documented by Ras *et al.,* who observed leptin-deficient db/db mice for 17 months and reported only mild pathological changes in the peripheral nerve fibers [301]. It is thus fair to say that a full clinical spectrum of the maturity-onset DPN likely requires a length of time exceeding the longevity of rodents to present and diabetic rodent models at best only help illustrate the very early aspects of the entire disease syndrome. Since none of the early pathogenetic pathways revealed in diabetic rodents will contribute to DPN in a quantitatively and temporally uniform fashion throughout the prolonged natural history of this disease, it is not surprising that a handful of inhibitors developed against these processes have not benefited patients with relatively long-standing neuropathy. As a matter of fact, any agents targeting single biochemical insults would be too little too late to treat a chronic neurological disorder with established nerve damage and pathogenetic heterogeneity (Figure 2). In DPN, such heterogeneity is the consequence of a complex interplay between genetic predisposition, physical characteristics, nutritional and other environmental factors. On the contrary, experi‐ mental rodents are maintained at a homogeneous genetic background. Genetic homogeneity becomes particularly apparent with the inbred strains and genetically engineered mice, making them more of a tool to elucidate the contribution of a specific component to disease development and less of a tool for an accurate prediction of the likelihood that a treatment will be effective for a general population. Apart from these internal factors, laboratory caged animals have an uniform dietary constitution, life cycle and environmental contact, therefore would not be exposed to the majority of the external risk factors otherwise incurred by individual patients, such as smoking and alcohol consumption [10]. Finally, humans have some unique behaviors that assume an integral part of DPN-associated complications but cannot be adopted by animals. This is perhaps the simplest reason why diabetic rodents are immune to gangrenous foot ulceration as upright walking has not evolved in these species.

therapeutic regimens ought to be sought. The invasive nature of present methods of biochem‐ ical, structural and functional measurements dictates that systemic and longitudinal assess‐ ments are not feasible in humans. To address this, miscellaneous rodent models have been created and used as substitutes for diabetic patients for the purpose of uncovering the pathogenetic mechanisms and testing potential pharmacological treatments. However, these conventional approaches have so far failed to yield a successful therapeutic translation. Further, animal surrogates are afflicted with species differences in genotype and behavior, nerve structure and metabolism, duration of diabetes, and tissue vulnerability, which allow limited transferability of animal results into clinical settings. It is important to point out that the present review does not argue against the ability of animal models to shed light on basic molecular, cellular and physiological processes that are shared among species. Undoubtedly, animal models of diabetes have provided abundant insights into the disease biology of DPN. Nevertheless, the lack of any meaningful advance in identifying a promising pharmacological target necessitates a reexamination of the validity of current DPN models as well as to offer a plausible alternative methodology to scientific approaches and disease intervention. After a critical reevaluation of the experimental results and clinical outcomes for several previously high-profile anti-DPN drugs, we conclude that the fundamental species differences have led to misinterpretation of rodent data and overall failure of pharmacological investment. As more is being learned, it is becoming prevailing that DPN is a chronic, heterogeneous disease unlikely to benefit from targeting specific and early pathogenetic components revealed by animal studies. Rather, an efficacious therapy must impact on multiple etiologic events and manage various risk factors. In this regard, rigorous lifestyle modulation may simultaneously intervene with a multitude of internal and external diabetogenic processes without generating significant tissue toxicity and side effects. Particularly, diet and exercise intervention provides an approach to improve metabolic management and enhance long-term reparative and regenerative capacity of diabetic nerves. Moreover, investigating the disease process via human-based study to the extent possible promises to lend much better insight into the pathology and pathogenesis of DPN as well as the clinical utility of potential treatments. We propose that future research should put an emphasis on advancing methodological and technological approaches that maximizes the access and utilization of human specimens under ethical guidelines, and on refining lifestyles for preventing and modifying DPN, which are more cost-effective and directly applicable to clinical practice in this otherwise largely

From Animal Models to Clinical Practicality: Lessons Learned from Current Translational Progress of…

http://dx.doi.org/10.5772/55364

51

This work is supported and funded by the Physicians Committee for Responsible Medicine. The authors thank Dr. Neal Barnard and Dr. Charu Chandrasekera for their help and expertise

intractable disorder.

on this paper.

**Acknowledgements**

**Figure 2. Schematic Demonstration of the Progressive Pathogenetic and Pathophysiological Changes in DPN.** Components highlighted in red marks changes that are often over-exaggerated in frequently used rodent models, whereas those in green mark physiological and morphological changes not replicated or misreplicated. Darker color in the triangle box indicates less likely the pathologies are to be adequately modeled in rodents. Double-headed arrows indicate interaction. PARP: poly(ADP-ribose) polymerase, MAPK: mitogen-activated protein kinase, ER: endoplastic re‐ ticulum.

### **4. Conclusion and outlook**

Needless to say, DPN has been a significant source of diabetes-induced mortality and mor‐ bidity that strike individuals, families and society with a staggering health and economic cost. There is little doubt that the need for effective DPN management is currently unmet and better therapeutic regimens ought to be sought. The invasive nature of present methods of biochem‐ ical, structural and functional measurements dictates that systemic and longitudinal assess‐ ments are not feasible in humans. To address this, miscellaneous rodent models have been created and used as substitutes for diabetic patients for the purpose of uncovering the pathogenetic mechanisms and testing potential pharmacological treatments. However, these conventional approaches have so far failed to yield a successful therapeutic translation. Further, animal surrogates are afflicted with species differences in genotype and behavior, nerve structure and metabolism, duration of diabetes, and tissue vulnerability, which allow limited transferability of animal results into clinical settings. It is important to point out that the present review does not argue against the ability of animal models to shed light on basic molecular, cellular and physiological processes that are shared among species. Undoubtedly, animal models of diabetes have provided abundant insights into the disease biology of DPN. Nevertheless, the lack of any meaningful advance in identifying a promising pharmacological target necessitates a reexamination of the validity of current DPN models as well as to offer a plausible alternative methodology to scientific approaches and disease intervention. After a critical reevaluation of the experimental results and clinical outcomes for several previously high-profile anti-DPN drugs, we conclude that the fundamental species differences have led to misinterpretation of rodent data and overall failure of pharmacological investment. As more is being learned, it is becoming prevailing that DPN is a chronic, heterogeneous disease unlikely to benefit from targeting specific and early pathogenetic components revealed by animal studies. Rather, an efficacious therapy must impact on multiple etiologic events and manage various risk factors. In this regard, rigorous lifestyle modulation may simultaneously intervene with a multitude of internal and external diabetogenic processes without generating significant tissue toxicity and side effects. Particularly, diet and exercise intervention provides an approach to improve metabolic management and enhance long-term reparative and regenerative capacity of diabetic nerves. Moreover, investigating the disease process via human-based study to the extent possible promises to lend much better insight into the pathology and pathogenesis of DPN as well as the clinical utility of potential treatments. We propose that future research should put an emphasis on advancing methodological and technological approaches that maximizes the access and utilization of human specimens under ethical guidelines, and on refining lifestyles for preventing and modifying DPN, which are more cost-effective and directly applicable to clinical practice in this otherwise largely intractable disorder.

### **Acknowledgements**

physical characteristics, nutritional and other environmental factors. On the contrary, experi‐ mental rodents are maintained at a homogeneous genetic background. Genetic homogeneity becomes particularly apparent with the inbred strains and genetically engineered mice, making them more of a tool to elucidate the contribution of a specific component to disease development and less of a tool for an accurate prediction of the likelihood that a treatment will be effective for a general population. Apart from these internal factors, laboratory caged animals have an uniform dietary constitution, life cycle and environmental contact, therefore would not be exposed to the majority of the external risk factors otherwise incurred by individual patients, such as smoking and alcohol consumption [10]. Finally, humans have some unique behaviors that assume an integral part of DPN-associated complications but cannot be adopted by animals. This is perhaps the simplest reason why diabetic rodents are immune to gangrenous foot ulceration as upright walking has not evolved in these species.

50 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

**Figure 2. Schematic Demonstration of the Progressive Pathogenetic and Pathophysiological Changes in DPN.** Components highlighted in red marks changes that are often over-exaggerated in frequently used rodent models, whereas those in green mark physiological and morphological changes not replicated or misreplicated. Darker color in the triangle box indicates less likely the pathologies are to be adequately modeled in rodents. Double-headed arrows indicate interaction. PARP: poly(ADP-ribose) polymerase, MAPK: mitogen-activated protein kinase, ER: endoplastic re‐

Needless to say, DPN has been a significant source of diabetes-induced mortality and mor‐ bidity that strike individuals, families and society with a staggering health and economic cost. There is little doubt that the need for effective DPN management is currently unmet and better

ticulum.

**4. Conclusion and outlook**

This work is supported and funded by the Physicians Committee for Responsible Medicine. The authors thank Dr. Neal Barnard and Dr. Charu Chandrasekera for their help and expertise on this paper.

### **Author details**

Chengyuan Li, Anne E. Bunner and John J. Pippin

Physicians Committee for Responsible Medicine, Washington, DC, USA

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**Chapter 3**

**New Insights on Neuropathic Pain Mechanisms as a**

Injuries affecting either the peripheral or the central nervous system (PNS, CNS) leads to neuropathic pain characterized by spontaneous pain and distortion or exaggeration of pain sensation. Peripheral nerve pathologies are considered generally easier to treat compared to those affecting the CNS, however peripheral neuropathies still remain a challenge to thera‐

Animal models such as denervation/neuroma formation [1], chronic constriction injury (CCI) by loose ligatures around the sciatic nerve [2], partial tight ligation of the sciatic nerve trunk (partial sciatic nerve ligation, PNL) [3]; tight ligature of L5 and L6 spinal nerves (spinal nerve ligation, SNL) [4]; section of one or two components of the sciatic nerve (spared nerve injury, SNI) [5]; streptozocin induced diabetic neuropathy [6] and peripheral neuropathy induced by vincristine or by anti-retroviral nucleoside analogue AIDS therapy drugs [7, 8] have been designed to mimic different neuropathic syndromes and reproduce in laboratory neuropathic pain main symptoms. Indeed all the mentioned neuropathic pain models show increased responses to thermal or mechanical nociceptive stimulation (hyperalgesia), hypersensitivity

to innocuous tactile or cold stimuli (allodynia) which lead to withdrawal behaviour.

A large body of studies has been accumulated during the last two decades to characterize and clarify mechanisms at the base of neuropathic pain development and maintenance. Peripheral

and reproduction in any medium, provided the original work is properly cited.

© 2013 Maione et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**2. Peripheral pathophysiology change mechanisms**

**Source for Novel Therapeutical Strategies**

Sabatino Maione, Enza Palazzo, Francesca Guida,

Livio Luongo, Dario Siniscalco, Ida Marabese,

Additional information is available at the end of the chapter

Francesco Rossi and Vito de Novellis

http://dx.doi.org/10.5772/55276

**1. Introduction**

peutic treatment.

