**5. Specific anti-inflammatory therapies**

#### **5.1 Therapies targeting pro-inflammatory transcription factor NF-**κ**B**

Many of the inflammatory mediators involved in inflammation and DA-neurodegeneration in PD are expressed in microglial cells and their regulation is primarily mediated by the transcription factor NF-κB. NF-κB was first described in 1986 as a transcription factor which is essential for the expression of mouse kappa light chain genes (Sen and Baltimore 1986; Sen and Baltimore 1986). It has since been shown that NF-κB functions to control gene expression of many of pro-inflammatory mediators (Tsoulfas and Geller 2001). Inflammatory cytokines such as TNFα and IL-1α and β, bacterial products such as lipopolysaccharide (LPS), and products of cellular damage strongly activate inflammatory responses through the activation of NF-κB. NF-κB subsequently plays an essential positivefeedback role in the inflammatory response through regulation of genes encoding inflammatory cytokines IL-1β, TNFα, and IL-12/23, as well as chemokines IL-8, MIP-1α, and MCP-1(Xia, Pauza et al. 1997; Roebuck 1999; Roebuck, Carpenter et al. 1999). NF-κB also mediates nitric oxide production (iNOS), expression of NADPH oxidase subunits p47 and p67 (Gauss, Nelson-Overton et al. 2007; Lawrence 2009), and adhesion molecules ICAM-1, VCAM, and E-selectin (Chen and Manning 1995; Tak and Firestein 2001). Activation of NFκB is a key event in many chronic inflammatory diseases such as cardiovascular disease (Van der Heiden, Cuhlmann et al.), tissue reperfusion injury (Latanich and Toledo-Pereyra 2009), experimental autoimmune encephalomyelitis (EAE) (Vandenbroeck, Alloza et al. 2004), rheumatoid arthritis (Criswell 2010), and inflammatory bowel disease (IBD) (Atreya, Atreya et al. 2008). A large number of the therapeutic agents for treating human inflammatory conditions, including sulfasalazine, 5-aminosalicylates, and corticosteroids, as well as some natural anti-inflammatory compounds such as IL-10, TGFβ1, β2AR agonists, glutamate, and curcumin, may owe their anti-inflammatory effects to inhibition of NF-κB (Lawrence and Fong ; Wang, Boddapati et al. ; Pereira and Oakley 2008; Lawrence 2009). These anti-inflammatory agents are potent inhibitors of microglial activation, and are neuroprotective to DA neurons *in vitro* and *in vivo*. Clearly, NF-κB activity presents a key target to ameliorate chronic inflammation in humans. Therapeutic strategies to inhibit NFκB activity in microglial cells may lead to more effective treatments for PD (Zhang, Qian et al. 2010; Flood, Qian et al. 2011).

The NF-κB family consists of dimeric transcription factors which include five members: c-Rel, RelA (p65), RelB, NF-κB1 (p50/p105), and NF-κB2 (p52/p100) (Flood, Qian et al. 2011). There are two major activation pathways: (1) the classical or canonical pathway, and (2) the

Inflammatory Responses and Regulation in Parkinson's Disease 387

neuroinflammation. The nature of the mechanism of NF-κB inhibition within the SN remains to be determined, but these data suggest NF-κB is a viable target for therapy for PD

A second approach to inhibit inflammation has been to use small molecule inhibitors that specifically block function of IKKβ. One such specific inhibitor, called Compound A, is a small molecule inhibitor of the kinase activity of IKKβ but not IKKα. Compound A, also known as BAY-65-1942 (7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]–5-[(3S)-3 piperidinyl]-1,4-dihydro-2Hpyrido [2,3- d] [1,3]–oxazin-2-one hydrochloride), has been shown to specifically and effectively block the catalytic activity of IKKβ, inhibiting its ability to phosphorylate IκB and activate the cytosolic p50/p65 NF-κB heterodimers (Moss, Stansfield et al. 2007; Zhang, Qian et al. 2010). In one recent study, Zhang and colleagues (2010) used Compound A in an LPS-induced neurodegeneration model to inhibit the canonical NF-κB pathway and halt inflammation-induced DA-neurodegeneration. In this model, LPS was injected directly into one side of the midbrain of rats, leading to inflammation-induced degeneration of DA-neurons (Zhang, Qian et al. 2010). It was found that Compound A strongly inhibited the activation of NF-κB *in vitro* and *in vivo*, as well as the mRNA expression and subsequent release of pro-inflammatory mediators. Compound A also significantly inhibited LPS- and MPTP-induced DA-neurotoxicity *in vitro*, and this neuroprotective activity required the presence of microglial cells. Most importantly, administration of Compound A to animals injected intranigrally with LPS, attenuated LPSinduced DA neuronal loss and microglia activation within the SN ((Zhang, Qian et al. ; Zhang, Qian et al. 2010). These data provide strong evidence that NF-κB offers a promising potential therapeutic target to halt DA-neurodegeneration, and that much additional work needs to be performed to determine the optimal approach and agent best suited for the

A family of compounds that have recently been shown to potentially reduce inflammation and DA-neurodegeneration in animal models are the β2 adrenergic receptor agonists. The β2 adrenergic receptor (β2AR) is a G-protein coupled receptor (GPCR) which is known to regulate of smooth muscle function in the airway and vasculature. Interestingly, β2AR expression has also been identified on immune cells such as macrophages, microglia, T cells, and B cells, and signaling through this receptor can inhibit the inflammatory response of these cells (Koff, Fann et al. 1986; Severn, Rapson et al. 1992; van der Poll, Jansen et al. 1994; Sekut, Champion et al. 1995; Panina-Bordignon, Mazzeo et al. 1997; Farmer and Pugin 2000; Kin and Sanders 2006). Both short-acting and long-acting β2AR agonists have been used for pharmacological studies and clinical therapy, and results have indicated that they possess the ability to inhibit the inflammatory responses by immune cells. Several of these longacting agonists such as salmeterol (Advair®) and formoterol (Symbicort®) are currently being used as anti-inflammatory therapeutics to treat asthma and chronic obstructive pulmonary disease (COPD) (Koto, Mak et al. 1996; Tashkin and Cooper 2004; McKeage and Keam 2009). However, potential use of β2AR agonists in neurodegenerative diseases in the CNS has not been well studied.Since most long-acting β2AR agonists are highly lipophilic and should readily cross the BBB, it is likely that these compounds could have an immunomodulatory effect on the progression of inflammation in PD patients by inhibiting

patients (Ghosh, Roy et al. 2007).

treatment of PD.

**5.2** β**2-AR agonists as PD therapeutics** 

alternate or noncanonical pathway. While the non-canonical pathway does not appear to play a major role in the activation of inflammation, the classical pathway is thought to regulate the production of most pro-inflammatory mediators and is characterized by activation of a dimer of Rel proteins p50 and p65. In the inactive state this Rel dimer is complexed within the cytosol to the inhibitory protein IκBα complex (Lawrence 2009). The classical NF-κB pathway is initiated upon phosphorylation, ubiquitination, and subsequent proteasome-dependent degradation of IκBα. The phosphorylation of IκBα on serine residues is mediated by IκB kinase (IKK), which is a molecular complex of three proteins consisting of a heterodimer of the two catalytic subunits IKKα and IKKβ, along with IKKγ (the NF-κB essential modulator, NEMO) (May, Marienfeld et al. 2002; Huxford and Ghosh 2009; Oeckinghaus and Ghosh 2009). Embryonic cells derived from genetic knock-out mice lacking IKKβ, IKKγ, or p65 are unresponsive to classical NF-κB inducers such as TNFα and IL-1β (Reuther-Madrid, Kashatus et al. 2002; Sizemore, Lerner et al. 2002; Sizemore, Agarwal et al. 2004). Activation of IKK in response to inflammatory mediators such as TNFα, IL-1β, and LPS, depends critically on the presence of the IKKγ (NEMO) subunit of the IKK complex (Rudolph, Yeh et al. 2000; May, Marienfeld et al. 2002), which results in the phosphorylation of the IκB by the kinase activity of IKKβ (Huxford and Ghosh 2009; Oeckinghaus and Ghosh 2009). An N-terminal region of NEMO associates with a hexapeptide sequence within the C-terminus of both IKKα and IKKβ (NEMO binding domain or NBD), and disruption or mutation of this NEMO-NBD interaction site on either IKKβ or IKKγ results in a loss of responsiveness of cells to pro-inflammatory signaling (Flood, Qian et al. 2011). Agents that block the activation of NF-κB are capable of inhibiting the two major inflammatory pathways in microglia—activation of oxidative stress and production of inflammatory mediators, including cytokines TNFα, IL-1β, IL-6, as well as chemokines associated with inflammation (Qian, Flood et al. 2010).

Selective IKKβ and IKKγ inhibitors that do not target IKKα or the non-canonical P100/p52 pathway, should be promising therapeutic agents for treating chronic inflammatory disorders including PD. Such specific NF-κB inhibitors have recently been used in murine models of PD to halt the progression of neurodegeneration induced by the neurotoxin MPTP (Ghosh, Roy et al. 2007), or by activation of CNS inflammation by the intracranial injection of LPS (Zhang, Qian et al. 2010). Pretreatment of animals with a peptide against the NEMO-binding domain (NBD peptide) prior to injection of MPTP into mice, significantly inhibits the activation of NF-κB within the midbrain region. This inhibition of NF-κB activation is accompanied by a concomitant reduction in inflammatory mediator mRNA expression within the SN, as well as the expression of microglial cell activation marker CD11b. Mice receiving the NBD peptide prior to MPTP injection also showed highly significant protection of the nigrostriatum from MPTP-induced neurodegeneration of the TH+ neurons and the loss of dopamine production, as well as improvement in their locomotor function compared with MPTP-injected mice given mutant peptide. More importantly, administration of NBD peptide 2 days after injection of MPTP showed substantial protection of TH+ neurons, suggesting that NBD peptide can be used therapeutically to slow down or halt the progression of DA-neurodegeneration in MPTPtreated animals (Ghosh, Roy et al. 2007). In addition, infrared analysis of the brains of NBDtreated animals determined that significant levels of the NBD peptide localized within the brain tissue, suggesting that the NBD peptide could cross the BBB and reach sites of

alternate or noncanonical pathway. While the non-canonical pathway does not appear to play a major role in the activation of inflammation, the classical pathway is thought to regulate the production of most pro-inflammatory mediators and is characterized by activation of a dimer of Rel proteins p50 and p65. In the inactive state this Rel dimer is complexed within the cytosol to the inhibitory protein IκBα complex (Lawrence 2009). The classical NF-κB pathway is initiated upon phosphorylation, ubiquitination, and subsequent proteasome-dependent degradation of IκBα. The phosphorylation of IκBα on serine residues is mediated by IκB kinase (IKK), which is a molecular complex of three proteins consisting of a heterodimer of the two catalytic subunits IKKα and IKKβ, along with IKKγ (the NF-κB essential modulator, NEMO) (May, Marienfeld et al. 2002; Huxford and Ghosh 2009; Oeckinghaus and Ghosh 2009). Embryonic cells derived from genetic knock-out mice lacking IKKβ, IKKγ, or p65 are unresponsive to classical NF-κB inducers such as TNFα and IL-1β (Reuther-Madrid, Kashatus et al. 2002; Sizemore, Lerner et al. 2002; Sizemore, Agarwal et al. 2004). Activation of IKK in response to inflammatory mediators such as TNFα, IL-1β, and LPS, depends critically on the presence of the IKKγ (NEMO) subunit of the IKK complex (Rudolph, Yeh et al. 2000; May, Marienfeld et al. 2002), which results in the phosphorylation of the IκB by the kinase activity of IKKβ (Huxford and Ghosh 2009; Oeckinghaus and Ghosh 2009). An N-terminal region of NEMO associates with a hexapeptide sequence within the C-terminus of both IKKα and IKKβ (NEMO binding domain or NBD), and disruption or mutation of this NEMO-NBD interaction site on either IKKβ or IKKγ results in a loss of responsiveness of cells to pro-inflammatory signaling (Flood, Qian et al. 2011). Agents that block the activation of NF-κB are capable of inhibiting the two major inflammatory pathways in microglia—activation of oxidative stress and production of inflammatory mediators, including cytokines TNFα, IL-1β, IL-6, as well as chemokines associated with

Selective IKKβ and IKKγ inhibitors that do not target IKKα or the non-canonical P100/p52 pathway, should be promising therapeutic agents for treating chronic inflammatory disorders including PD. Such specific NF-κB inhibitors have recently been used in murine models of PD to halt the progression of neurodegeneration induced by the neurotoxin MPTP (Ghosh, Roy et al. 2007), or by activation of CNS inflammation by the intracranial injection of LPS (Zhang, Qian et al. 2010). Pretreatment of animals with a peptide against the NEMO-binding domain (NBD peptide) prior to injection of MPTP into mice, significantly inhibits the activation of NF-κB within the midbrain region. This inhibition of NF-κB activation is accompanied by a concomitant reduction in inflammatory mediator mRNA expression within the SN, as well as the expression of microglial cell activation marker CD11b. Mice receiving the NBD peptide prior to MPTP injection also showed highly significant protection of the nigrostriatum from MPTP-induced neurodegeneration of the TH+ neurons and the loss of dopamine production, as well as improvement in their locomotor function compared with MPTP-injected mice given mutant peptide. More importantly, administration of NBD peptide 2 days after injection of MPTP showed substantial protection of TH+ neurons, suggesting that NBD peptide can be used therapeutically to slow down or halt the progression of DA-neurodegeneration in MPTPtreated animals (Ghosh, Roy et al. 2007). In addition, infrared analysis of the brains of NBDtreated animals determined that significant levels of the NBD peptide localized within the brain tissue, suggesting that the NBD peptide could cross the BBB and reach sites of

inflammation (Qian, Flood et al. 2010).

neuroinflammation. The nature of the mechanism of NF-κB inhibition within the SN remains to be determined, but these data suggest NF-κB is a viable target for therapy for PD patients (Ghosh, Roy et al. 2007).

A second approach to inhibit inflammation has been to use small molecule inhibitors that specifically block function of IKKβ. One such specific inhibitor, called Compound A, is a small molecule inhibitor of the kinase activity of IKKβ but not IKKα. Compound A, also known as BAY-65-1942 (7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]–5-[(3S)-3 piperidinyl]-1,4-dihydro-2Hpyrido [2,3- d] [1,3]–oxazin-2-one hydrochloride), has been shown to specifically and effectively block the catalytic activity of IKKβ, inhibiting its ability to phosphorylate IκB and activate the cytosolic p50/p65 NF-κB heterodimers (Moss, Stansfield et al. 2007; Zhang, Qian et al. 2010). In one recent study, Zhang and colleagues (2010) used Compound A in an LPS-induced neurodegeneration model to inhibit the canonical NF-κB pathway and halt inflammation-induced DA-neurodegeneration. In this model, LPS was injected directly into one side of the midbrain of rats, leading to inflammation-induced degeneration of DA-neurons (Zhang, Qian et al. 2010). It was found that Compound A strongly inhibited the activation of NF-κB *in vitro* and *in vivo*, as well as the mRNA expression and subsequent release of pro-inflammatory mediators. Compound A also significantly inhibited LPS- and MPTP-induced DA-neurotoxicity *in vitro*, and this neuroprotective activity required the presence of microglial cells. Most importantly, administration of Compound A to animals injected intranigrally with LPS, attenuated LPSinduced DA neuronal loss and microglia activation within the SN ((Zhang, Qian et al. ; Zhang, Qian et al. 2010). These data provide strong evidence that NF-κB offers a promising potential therapeutic target to halt DA-neurodegeneration, and that much additional work needs to be performed to determine the optimal approach and agent best suited for the treatment of PD.

#### **5.2** β**2-AR agonists as PD therapeutics**

A family of compounds that have recently been shown to potentially reduce inflammation and DA-neurodegeneration in animal models are the β2 adrenergic receptor agonists. The β2 adrenergic receptor (β2AR) is a G-protein coupled receptor (GPCR) which is known to regulate of smooth muscle function in the airway and vasculature. Interestingly, β2AR expression has also been identified on immune cells such as macrophages, microglia, T cells, and B cells, and signaling through this receptor can inhibit the inflammatory response of these cells (Koff, Fann et al. 1986; Severn, Rapson et al. 1992; van der Poll, Jansen et al. 1994; Sekut, Champion et al. 1995; Panina-Bordignon, Mazzeo et al. 1997; Farmer and Pugin 2000; Kin and Sanders 2006). Both short-acting and long-acting β2AR agonists have been used for pharmacological studies and clinical therapy, and results have indicated that they possess the ability to inhibit the inflammatory responses by immune cells. Several of these longacting agonists such as salmeterol (Advair®) and formoterol (Symbicort®) are currently being used as anti-inflammatory therapeutics to treat asthma and chronic obstructive pulmonary disease (COPD) (Koto, Mak et al. 1996; Tashkin and Cooper 2004; McKeage and Keam 2009). However, potential use of β2AR agonists in neurodegenerative diseases in the CNS has not been well studied.Since most long-acting β2AR agonists are highly lipophilic and should readily cross the BBB, it is likely that these compounds could have an immunomodulatory effect on the progression of inflammation in PD patients by inhibiting

Inflammatory Responses and Regulation in Parkinson's Disease 389

intervention to top the chronic inflammatory response, including introduction of antiinflammatory drugs, compounds, cytokines and Treg cells, which inherently release anti-

Fig. 1. Model relating chronic inflammation to dopaminergic (DA)-neuron death in

Five relatively new approaches in anti-inflammatory therapy described above all show some promise for short-term or long-term therapeutics in PD. The use of exogenous antiinflammatory cytokines such as IL10 or TGFβ1, has been shown to have potent effects in reducing neurotoxicity in both *in vitro* and in animal models of PD. However, although both cytokines are considered to be predominantly anti-inflammatory, they each can have pro-inflammatory effects in certain contexts. More thorough functional studies are needed for these anti-inflammatory cytokines, especially in the context of PD models before these might be readily used in human therapy. Particularly important factors include what form and what mode of delivery will optimize the anti-inflammatory effects of the cytokines as therapy and ameliorate any unintended negative effects. Cell-based therapies such as regulatory T cells (Tregs) offer great promise for long-term therapy in many degenerative disorders including PD. Both the use of T cells and stem cell transplantation focus on regeneration as well as intervening in neuronal death processes. However, some of the

inflammatory cytokines such as TGFβ1 and IL-10.

Parkinson's Disease.

**7. Future directions for PD therapy** 

the activation of microglia that normally express high levels of β2AR (Tanaka, Kashima et al. 2002).

When long-acting β2AR agonists were tested for DA-neuroprotective properties, it was found that the compounds can inhibit DA-neurodegeneration *in vitro,* even if used at extremely low doses. Furthermore, administration of the long-acting β2AR agonist salmeterol significantly protects DA neurons against LPS- and MPTP-induced cytotoxicity *in vivo* (Qian, Wu et al. 2011). Mechanistic studies using primary midbrain neuron-glia cultures demonstrated that salmeterol, as well as several other long-acting β2AR agonists, have potent neuroprotective effects through their inhibition of microglial inflammatory mediator production. These antiinflammatory effects of salmeterol require the presence of β2AR, are mediated through the inhibition of both MAPK and NF-κB signaling pathways in activated microglia, and function independently of the canonical GPCR/cAMP/PKA signaling pathway. It was further determined that this inhibition is dependent on the expression of β-arrestin 2, which suggests a novel mechanism for the long-acting β2ΑR agonists in regulating CNS inflammatory conditions (Qian, Wu et al. 2011). Therefore, the high specific activity and effectiveness of β2AR agonists such as salmeterol at inhibiting inflammation and DA-neurodegeneration within the CNS in these animal models suggests they have potential for the treatment of chronic inflammatory disorders and in particular, Parkinson's disease.

### **6. Proposed model of neuroinflammation in PD**

Inflammation associated with PD can be initiated in the brain by internal factors such as a brain injury, a genetic mutation or some other brain insult or dysfunction (Nagatsu and Sawada 2006; Tansey, McCoy et al. 2007; Hirsch and Hunot 2009; Qian, Flood et al. 2010)(Figure 1). These sorts of intracerebral inflammatory stimuli activate the microglia which then up-regulate production of inflammatory factors including inflammatory cytokines such as TNFα, IL-1β or IL-6, as well as NO and ROS (Nagatsu, Mogi et al. 2000; Nagatsu and Sawada 2006; Tansey, McCoy et al. 2007). These in turn stimulate a further inflammatory response which results in a self-perpetuating chronic inflammatory condition (Qian and Flood 2008; Qian, Flood et al. 2010). Alternatively, inflammation in the periphery might induce the initial inflammatory response within the brain. Normally, the microvascular endothelial cells that line the blood vessels in the brain are tightly joined to each other through cell-cell tight junctions, and thus form the blood-brain-barrier which excludes most substances or cells from entry into the brain (Zlokovic 2008). A chronic peripheral inflammatory response can work to disrupt the cell-cell junctions and the bloodbrain barrier, allowing access of inflammatory factors and cells into the brain (Stamatovic, Keep et al. 2008; Zlokovic 2008). These can then activate microglia and initiate the perpetual round of pro-inflammatory factor production leading to chronic neuroinflammation. Once microglia are activated, from whatever the source of initial inflammatory stimulus, the microglial response increases secretion of inflammatory cytokines and release of NO (Qian and Flood 2008). Microglial activation also precipitates an enhanced respiratory burst and release of ROS (Colton and Gilbert 1987). These various inflammatory mediators can trigger cell death in neurons (Chao, Hu et al. 1992; Colton and Gilbert 1993; Taylor, Jones et al. 2005), including DA neurons which seem to be especially vulnerable. Dying neurons then stimulate an intensified inflammatory response as the brain attempts to restore stasis (Qian, Flood et al. 2010). Therapies aimed at halting neurodegeneration are increasingly based on

the activation of microglia that normally express high levels of β2AR (Tanaka, Kashima et al.

When long-acting β2AR agonists were tested for DA-neuroprotective properties, it was found that the compounds can inhibit DA-neurodegeneration *in vitro,* even if used at extremely low doses. Furthermore, administration of the long-acting β2AR agonist salmeterol significantly protects DA neurons against LPS- and MPTP-induced cytotoxicity *in vivo* (Qian, Wu et al. 2011). Mechanistic studies using primary midbrain neuron-glia cultures demonstrated that salmeterol, as well as several other long-acting β2AR agonists, have potent neuroprotective effects through their inhibition of microglial inflammatory mediator production. These antiinflammatory effects of salmeterol require the presence of β2AR, are mediated through the inhibition of both MAPK and NF-κB signaling pathways in activated microglia, and function independently of the canonical GPCR/cAMP/PKA signaling pathway. It was further determined that this inhibition is dependent on the expression of β-arrestin 2, which suggests a novel mechanism for the long-acting β2ΑR agonists in regulating CNS inflammatory conditions (Qian, Wu et al. 2011). Therefore, the high specific activity and effectiveness of β2AR agonists such as salmeterol at inhibiting inflammation and DA-neurodegeneration within the CNS in these animal models suggests they have potential for the treatment of

Inflammation associated with PD can be initiated in the brain by internal factors such as a brain injury, a genetic mutation or some other brain insult or dysfunction (Nagatsu and Sawada 2006; Tansey, McCoy et al. 2007; Hirsch and Hunot 2009; Qian, Flood et al. 2010)(Figure 1). These sorts of intracerebral inflammatory stimuli activate the microglia which then up-regulate production of inflammatory factors including inflammatory cytokines such as TNFα, IL-1β or IL-6, as well as NO and ROS (Nagatsu, Mogi et al. 2000; Nagatsu and Sawada 2006; Tansey, McCoy et al. 2007). These in turn stimulate a further inflammatory response which results in a self-perpetuating chronic inflammatory condition (Qian and Flood 2008; Qian, Flood et al. 2010). Alternatively, inflammation in the periphery might induce the initial inflammatory response within the brain. Normally, the microvascular endothelial cells that line the blood vessels in the brain are tightly joined to each other through cell-cell tight junctions, and thus form the blood-brain-barrier which excludes most substances or cells from entry into the brain (Zlokovic 2008). A chronic peripheral inflammatory response can work to disrupt the cell-cell junctions and the bloodbrain barrier, allowing access of inflammatory factors and cells into the brain (Stamatovic, Keep et al. 2008; Zlokovic 2008). These can then activate microglia and initiate the perpetual round of pro-inflammatory factor production leading to chronic neuroinflammation. Once microglia are activated, from whatever the source of initial inflammatory stimulus, the microglial response increases secretion of inflammatory cytokines and release of NO (Qian and Flood 2008). Microglial activation also precipitates an enhanced respiratory burst and release of ROS (Colton and Gilbert 1987). These various inflammatory mediators can trigger cell death in neurons (Chao, Hu et al. 1992; Colton and Gilbert 1993; Taylor, Jones et al. 2005), including DA neurons which seem to be especially vulnerable. Dying neurons then stimulate an intensified inflammatory response as the brain attempts to restore stasis (Qian, Flood et al. 2010). Therapies aimed at halting neurodegeneration are increasingly based on

chronic inflammatory disorders and in particular, Parkinson's disease.

**6. Proposed model of neuroinflammation in PD** 

2002).

intervention to top the chronic inflammatory response, including introduction of antiinflammatory drugs, compounds, cytokines and Treg cells, which inherently release antiinflammatory cytokines such as TGFβ1 and IL-10.

Fig. 1. Model relating chronic inflammation to dopaminergic (DA)-neuron death in Parkinson's Disease.
