The Pesticide Chlordecone Promotes Parkinsonism-like Neurodegeneration with Tau Lesions in Midbrain Cultures and C. elegans Worms.

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson's disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomotor deficits secondary to alterations in food perception. L-DOPA, a molecule used for PD treatment, corrected these deficits. Cholinergic and serotoninergic neuronal cells were also affected by CLD in C. elegans, although to a lesser extent than DA neurons. Noticeably, CLD also promoted the phosphorylation of the aggregation-prone protein tau (but not of α-synuclein) both in midbrain cell cultures and in a transgenic C. elegans strain expressing a human form of tau in neurons. In summary, our data suggest that CLD is more likely to promote atypical forms of Parkinsonism characterized by tau pathology than classical synucleinopathy-associated PD.

Effects of a New Natural Catechol-O-methyl Transferase Inhibitor on Two In Vivo Models of Parkinson's Disease.

A tetrahydroisoquinoline identified in Mucuna pruriens ((1R,3S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid, compound 4) was synthesized and assessed for its in vitro pharmacological profile and in vivo effects in two animal models of Parkinson's disease. Compound 4 inhibits catechol-O-methyltransferase (COMT) with no affinity for the dopaminergic receptors or the dopamine transporter. It restores dopamine-mediated motor behavior when it is co-administered with L-DOPA to C. elegans worms with 1-methyl-4-phenylpyridinium-damaged dopaminergic neurons. In a 6-hydroxydopamine rat model of Parkinson's disease, its co-administration at 30 mg/kg with L-DOPA enhances the effect of L-DOPA with an intensity similar to that of tolcapone 1 at 30 mg/kg but for a shorter duration. The effect is not dose-dependent. Compound 4 seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound 4 further validates the traditional use of M. pruriens for the treatment of Parkinson's disease, and compound 4 can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.