A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson's disease and potential molecular targets

Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc). The specific molecular events that cause PD are currently not known; however, progress to better understand PD pathogenesis has been made using various animal models of the disease. In this review, we have highlighted reports from 2012 in which neurochemical/neurotoxins have been used in rodents to specifically address the role of neuroinflammation in the development and/or progression of PD-like pathology and in particular nigral degeneration. A number of studies have been summarized in which plausible pro-inflammatory, anti-inflammatory, or therapeutic agents targeting inflammatory pathways were introduced and/or investigated by various groups for neuroprotective effects. From these studies, it is clear that neuroinflammation acts to exacerbate the toxic outcomes that are set in motion within neurons following exposure to neurotoxins. Additionally, it is noted that future work is still needed to better understand the underlying mechanisms mediating the neuroinflammatory and neurotoxic phenotypes reported in rodent models of PD-like pathology to maximize the translation potential of these interventions to the clinic to prevent and/or delay PD onset and/or progression in humans.

Parkinson’s disease and enhanced inflammatory response

“…MPPþ utilizes the dopamine transporter to selectively target DA neurons where MPPþ inhibits mitochondrial complex I causing increased ROS and neuron demise. 20,50 However, the mechanism of death may be more complicated in light of evidence implicating inflammatory response in MPTP toxicity. MPTP treatment of mice leads to loss of DA neuron cell bodies in the SN and axon terminals in the striatum as well as reduced dopamine levels.…”

“…Evidence also suggests that PD modeling neurotoxins such as MPTP facilitate DA neuron loss at least in part by induction of inflammatory response. 20 Additionally, in mice, enhanced inflammation has been shown to recapitulate a-synuclein aggregation and oxidation in affected neurons. 18,21 A large clinical study also reported that discontinuation of lipophilic statins correlated with an elevated incidence of PD.…”

“…48 MPTP is a lipophilic agent that can traverse the BBB. 20,49 Once inside the brain parenchyma, MPTP may be processed to MPPþ, the active toxin, by monoamine oxidase-B (MAOB) activity in glial cells. MPPþ utilizes the dopamine transporter to selectively target DA neurons where MPPþ inhibits mitochondrial complex I causing increased ROS and neuron demise.…”

“…It is believed that 6-OHDA is imported into DA neurons by dopamine reuptake transporters. 20 Unlike MPTP, 6-OHDA cannot traverse the BBB and therefore must be administered through stereotactic injection into the striatum or SN. Upon entry into neurons, 6-OHDA auto-oxidizes to generate ROS and quinones leading to oxidative damage and neuronal death.…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…This inflammatory model of PD suggest that inflammatory stress can manifest in DA neuron loss likely through infiltration of peripheral leukocytes. Related to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model, it has been described that this neurotoxin facilitate dopamine neuronal loss at least in part by induction of inflammatory response [42]. Also, in mice, enhanced inflammation has been shown to recapitulate α-synuclein aggregation and oxidation in affected neurons [43].…”