Environmental Toxins and Dopaminergic Neurotoxicity: Novel Neuroprotective Strategies

Abstract

Parkinson's disease (PD) is a progressive degeneration of dopaminergic neurons in the substantia nigra, leading to massive loss of dopamine in the striatum. Environmental and endogenous neurotoxins are implicated the etiopathology and progression of nigral neurodegeneration in PD. Animal models are an important aid to study pathogenic mechanisms, nature of behavioral abnormalities with respect to neurotransmitters changes in the brain and also provides a better understanding to design novel therapeutic drugs and devise neuroprotective strategies. Diquat is a herbicide, which structurally resembles MPTP/paraquat. Dopamine-derived endogenous neurotoxin salsolinol is also involved in the pathogenesis of PD. We evaluated the effect of diquat and/or salsolinol (chronic exposure) on the nigrostriatal dopaminergic system in mice. However, diquat and/or salsolinol affected the behavior but did not induce any dopamine depletion in the striatum. 1-methyl-4-pheneyl-1,2,3,6-terahydropriydine (MPTP) is a potent neurotoxin that causes selective loss of dopaminergic neurons and causing PD like symptoms. PD animal model was induced in mice by systemic injection of MPTP and then we investigated the behavioral, neurochemical, biochemical and neuropathological hallmarks of the disease. Inflammation, oxidative stress, mitochondrial dysfunction, and altered GABA levels are associated with progressive nigrostriatal neurodegeneration. Adenosine receptor and peroxisome proliferator-activated receptors (PPAR) play an important role in the modulation of inflammation and GABA. Adenosine receptor antagonist, PPAR-modulators and anti-inflammatory drugs have shown to decrease inflammation which can lead to neuroprotection. However, the effect of these drugs on GABA and its role in neuroprotection is not clear. Thus in this study we investigated the various neuroprotective mechanisms (antioxidant activity, effect on GABA and mitochondrial energy enhancing properties) of Caffeine (adenosine A2 receptor antagonist), Dexamethasone (Anti-inflammatory), and GW501516 (PPAR agonist), against MPTP-induced neurotoxicity. Caffeine and dexamethasone significantly improved the behavioral defect induced by MPTP, scavenged the free radical and altered the major endogenous antioxidant molecules and striatal GABA levels leading to neuroprotection. However, GW501516 prevented the development of motor impairment, decreased oxidative stress, without altering GABA attenuated MPTP-induced dopamine depletion. Thus, in the present study we investigated the various neuroprotective mechanisms of drugs with anti-inflammatory effect against MPTP-induced neurotoxicity.