*3.2.2 Minocycline*

Minocycline is a second generation tetracycline, a semi-synthetic antibiotic able to cross blood brain barrier, and it can be used to treat rheumatoid arthritis [95, 96]. Minocycline has neuroprotective effects when administered during the acute neural trauma. Current data suggest that minocycline has anti-inflammatory, immunomodulatory, and neuroprotective effects. These beneficial actions are achieved as a result of the inhibition of iNOS matrix metalloproteinases (MMPs), PLA2, TNF-α, caspase-1, and caspase-3. Moreover, minocycline enhances Bcl-2 and thus, reduces apoptosis, also, it decreases p38 mitogen-activated protein kinase (MAPK) phosphorylation and inhibits PARP-1 [97–100]. Other studies report that minocycline can bind to Ca+2 and Mg+ , reduces reactive astrocytes to increase oligodendrocyte viability in white matter, and inhibits the activation of microglial cells [101, 102]. A multi-center phase II trial was performed to explore the neuroprotective effect of minocycline; however, the results of the study did not establish a real improvement in SCI. Authors suggest further investigations in a multi-center phase III trial [103].

**167**

*Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art*

**Treatment outcome Ref.**

MP may cause acute corticosteroid myopathy, at doses recommended by the NASCIS. [92]

[89]

[86]

[90]

[91]

[55]

[93]

[94]

NASCIS I: Treatment with a dose 1.0 g daily promotes neurological recovery. The morbidity and

NASCIS II: Administration of (30 mg/kg intravenous bolus plus 23 hour infusion of 5.4 mg/kg) during the first 8 hours after injury causes neurological recovery seen from 6 weeks after the SCI.

NASCIS III: Administration within 8 hours from the SCI, should maintain the administration for

Combination of riluzole and MP improves functional recovery and tissue sparing. In addition,

High-dose MP inhibits glucocorticoid receptors as well as having effects in LPO; however, their

Administration of MP for treatment of SCI is not recommended. There is evidence that high-dose

A comparative study of MP vs. A91-immunization showed that A91-immunization has a better efficiency promoting motor recovery. Combining MP with A91-immunization allowed to observe that MP has a transient immunosuppressive effect that eliminated the beneficial actions of

Gangliosides (GM-1) are sialic acid-containing glycosphingolipids, present in cell membranes of CNS cells, specifically in the external leaflet of plasma membranes. They participate in the repair and maintenance of CNS [104, 105]. A randomized placebo-controlled (Phase II) trial with administration of GM-1 within 24 hours after injury was realized in 37 patients with SCI. The results of this study showed that GM-1 enhances the recovery of neurologic function after 1 year [104]. Further studies should be designed in order to provide more evidence about the

Glyburide (glibenclamide) is a FDA approved sulfonylurea drug widely used to treat type 2 diabetes; it has the ability to target receptor (SUR1) regulated Ca+2 activated [ATP] cation (NCCa-ATP) channels [96, 106]. After SCI, there are small hemorrhagic lesions at the epicenter of gray matter. Glyburide diminishes the progressive hemorrhage necrosis by jamming the interaction between SUR-1 and preforming subunits of NCCa-ATP channels located in endothelial cells. In addition, improves neurological function [107]. Actually, a phase I/II clinical trial is currently under way to test the safety and neuroprotective effectiveness of glyburide in

The most common preclinical nonpharmacological therapies in the acute phase of SCI are antioxidants, growth factors, and transplant of cultured cells like neural stem cells (NSCs), bone marrow stem cells (BMSCs), olfactory ensheathing cells

**4. Nonpharmacological therapies (preclinical interventions)**

*DOI: http://dx.doi.org/10.5772/intechopen.89539*

48 hours to improve neurological function.

*Effects of methylprednisolone in spinal cord injury.*

beneficial effects on oxidative stress were observed.

beneficial effects are independent of LPO inhibition.

steroids are associated with harmful side effects including death.

mortality is increased.

*3.2.3 GM-1-ganglioside*

A91-immunization.

**Table 2.**

efficacy of GM-1.

patients with SCI [88].

(OECs), and Schwann cells (SCs).

*3.2.4 Glyburide*

*Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art DOI: http://dx.doi.org/10.5772/intechopen.89539*


#### **Table 2.**

*Neuroprotection - New Approaches and Prospects*

effective alternative after SCI.

*3.2.1 Methylprednisolone*

*3.2.2 Minocycline*

**3.2 Clinical pharmacological therapies**

expression of cytoskeletal proteins, promoting them as an increasing in neurite outgrowth [77, 78]. Studies in rats treated with estradiol have shown a reduction in the lesion size, an increase in white matter sparing, and an improving in motor function [77, 79, 80]. On the other hand, testosterone has shown to exert similar but not identical effects; it is neuroprotective against apoptosis in oxidative stress [77, 78]. A study with young adult female rats implanted with testosterone-filled silastic capsules reported regressive changes in motoneuron and muscle morphology after a SCI providing the possibility of improving motor function [81]. A study with administration of progesterone in rats improves neurological deficits and reduces inflammatory response. Prevents degeneration of motor neurons and reestablishes proliferation and differentiation of oligodendrocytes [82]. At the moment, investigations on the field conclude that gonadal hormones could be an

Methylprednisolone, minocycline, GM-1-ganglioside, and glyburide are some of

Methylprednisolone (MP) is a synthetic glucocorticoid, with anti-inflammatory and anti-oxidant effects [83, 84]. MP blocks the inflammatory cascade and disrupts neuron regeneration by inhibiting immunological cells [85, 86]. The potential neuroprotective effects of MP have been reported especially in the acute phase of SCI. According to some investigations, MP is capable of reducing FR production, Ca+2 influx, excitotoxicity, and immune-mediated phagocytosis over the course of hypoperfusion of SCI [87]. In addition, MP appears to have effect in apoptosis and autophagy regulation; however, the mechanisms are not clear [84]. While it remains the only option for acute SCI treatment in clinical settings, a debate regarding optimal dose, time of administration, efficacy, and adverse effects has dominated the field for years. There are three National Acute SCI Studies (NASCIS) and other clinical or biomedical investigations, in which the safety and efficacy of MP were assessed (**Table 2**) [88]. Despite the intense investigation, currently there is an

Minocycline is a second generation tetracycline, a semi-synthetic antibiotic able to cross blood brain barrier, and it can be used to treat rheumatoid arthritis [95, 96]. Minocycline has neuroprotective effects when administered during the acute neural trauma. Current data suggest that minocycline has anti-inflammatory, immunomodulatory, and neuroprotective effects. These beneficial actions are achieved as a result of the inhibition of iNOS matrix metalloproteinases (MMPs), PLA2, TNF-α, caspase-1, and caspase-3. Moreover, minocycline enhances Bcl-2 and thus, reduces apoptosis, also, it decreases p38 mitogen-activated protein kinase (MAPK) phosphorylation and inhibits PARP-1 [97–100]. Other studies

increase oligodendrocyte viability in white matter, and inhibits the activation of microglial cells [101, 102]. A multi-center phase II trial was performed to explore the neuroprotective effect of minocycline; however, the results of the study did not establish a real improvement in SCI. Authors suggest further investigations in a

, reduces reactive astrocytes to

the most investigated pharmacological therapies in clinical settings.

important controversy regarding the real utility of this drug.

report that minocycline can bind to Ca+2 and Mg+

multi-center phase III trial [103].

**166**

*Effects of methylprednisolone in spinal cord injury.*

#### *3.2.3 GM-1-ganglioside*

Gangliosides (GM-1) are sialic acid-containing glycosphingolipids, present in cell membranes of CNS cells, specifically in the external leaflet of plasma membranes. They participate in the repair and maintenance of CNS [104, 105]. A randomized placebo-controlled (Phase II) trial with administration of GM-1 within 24 hours after injury was realized in 37 patients with SCI. The results of this study showed that GM-1 enhances the recovery of neurologic function after 1 year [104]. Further studies should be designed in order to provide more evidence about the efficacy of GM-1.

#### *3.2.4 Glyburide*

Glyburide (glibenclamide) is a FDA approved sulfonylurea drug widely used to treat type 2 diabetes; it has the ability to target receptor (SUR1) regulated Ca+2 activated [ATP] cation (NCCa-ATP) channels [96, 106]. After SCI, there are small hemorrhagic lesions at the epicenter of gray matter. Glyburide diminishes the progressive hemorrhage necrosis by jamming the interaction between SUR-1 and preforming subunits of NCCa-ATP channels located in endothelial cells. In addition, improves neurological function [107]. Actually, a phase I/II clinical trial is currently under way to test the safety and neuroprotective effectiveness of glyburide in patients with SCI [88].

#### **4. Nonpharmacological therapies (preclinical interventions)**

The most common preclinical nonpharmacological therapies in the acute phase of SCI are antioxidants, growth factors, and transplant of cultured cells like neural stem cells (NSCs), bone marrow stem cells (BMSCs), olfactory ensheathing cells (OECs), and Schwann cells (SCs).
