**5. Neuroinflammation**

Neuroinflammation in PD is characterized by microgliosis and astrogliosis increased around the dopaminergic neurons in SNpc [61]. These cellular process promotes high levels of expression of major histocompatibility complex type II (MHC-II) [62], chemokine receptors, integrins, neurotrophins and several other markers [63]. Elevated levels of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), nitric oxide and reactive oxygen or nitrogen species (ROS/RNS) by NADPH oxidase system or by mitochondria are also observed in PD patients [31, 64]. Recently it has been demonstrated that copperzinc superoxide dismutase (SOD1) released by microglial cells, or a TNF receptor 2 selective agonist, could confer neuroprotection against 6-OHDA toxicity *in vivo* [65, 66].

Injury of CNS leads to cell death, cellular swelling, excitotoxicity and the release of free radicals and nitric oxide, which triggers a strong glial response [67, 68] referred as reactive gliosis, involving the activation of microglia, astrocytes, oligodendrocytes and Neuron/glial 2 (NG2) cells [69, 70]. After injury, mature astrocytes proliferate and acquire stem cell properties suggesting their capacity to promote regeneration [71]. Depending on the stimulus and intensity of the lesion, all the three types of glia directs the cell either toward the neuroprotection by producing neurotrophic factors or toward the neurodegeneration by producing apoptotic mediators and ROS/RNS. However, NG2 cells, with their neurogenic [72], oligodendrogenic [73], astrogenic [74] and microgliogenic properties play indirect role in directing the cell toward apoptosis or protection. The presence of NG2-positive cells has been identified in SNpc but not in the striatum of the rat [75]. A recent study in a murine paradigm showed that conversion of NG2 cells to astrocytes to produce cerebral dopamine neurotrophic factor (CDNF) is anti-inflammatory in 6-OHDA-induced rat PD model [76]. However, studying the role, mode of activation and conversion of NG2 cells could give further clues to the field of neuroinflammation.

The neuroinflammatory process has been evaluated through glial cell markers such as glial fibrillary acidic protein (GFAP) for astrocytes [77, 78] and OX-42 or Iba-1 antibodies to microglia [79, 80]. The temporal course of activation of these glial populations has been determined by the neurotoxic effect, from day 3 post-injury [51], and even its activation was observed up to 3 weeks after injury with 6-OHDA [78]. The neuroinflammatory process to that precedes the death of nigral dopaminergic neurons (2 weeks post-injury) is probably a mechanism indicating cell damage. Another body of evidence suggests that the increase in the activation of glial cells, and the consequent release of pro- and anti-inflammatory cytokines at the site of damage, could increase the cytotoxicity of 6-OHDA [26]. Overexpression of human alpha-synuclein in a mouse model of PD showed enhanced expression of proinflammatory cytokines and microglial activation [81]. Recently, the studies focused on NG2 cells, mitochondrial dysfunction or Lewy body accumulation (trend topic based in alpha-synuclein model) has been relevant to understand neuroinflammatory process and define alternative therapeutic targets for PD.
