Abstract
Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility. At the end of the experiment, brainstem and midbrain tissues were analyzed for the presence of misfolded α-synuclein and neuronal loss in the SNpc and in the dorsal motor nucleus of the vagus (DMV). Misfolded α-synuclein was found in DMV and SNpc neurons. A significant decrease in tyrosine hydroxylase positive dopaminergic neurons was noted in the SNpc, conversely there was no apparent loss of cholinergic neurons of the DMV. Nigrovagally-evoked gastric motility was impaired in treated rats prior to the onset of parkinsonism, the motor deficits of which were improved by l-dopa treatment. Vagotomy prevented the development of parkinsonian symptoms and constrained the appearance of misfolded α-synuclein to myenteric neurons. These data demonstrate that co-administration of subthreshold doses of paraquat and lectin induces progressive, l-dopa-responsive parkinsonism that is preceded by gastric dysmotility. This novel preclinical model of environmentally triggered PD provides functional support for Braak’s staging hypothesis of idiopathic PD.
Highlights
While the etiology of Parkinson’s disease (PD) is unknown, both genetic and environmental factors have been theorized to play a role in its pathogenesis
A significant amelioration of Parkinsonism was evident after four doses of Ldopa, with an increase in vibrissae test scores to 8.3 ± 0.65 successful forelimb placement/10 trials (p < 0.05 vs. paraquat + lectin; p > 0.05 vs. baseline), supporting the hypothesis that exposure to subthreshold doses of paraquat + lectin induces ongoing nigrostriatal dopaminergic degeneration that is reversibly ameliorated with L-dopa treatment (Fig. 4a)
We demonstrated that co-administration of subthreshold doses of lectin + paraquat produce (i) consistent pathological hallmarks of α-synuclein aggregation in enteric, brainstem, and midbrain neurons, (ii) stable parkinsonism associated with modest, but significant, degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons, and (iii) motor parkinsonism is reversibly treatable with L-dopa
Summary
While the etiology of Parkinson’s disease (PD) is unknown, both genetic and environmental factors have been theorized to play a role in its pathogenesis. Disruption of this nigro-vagal circuit may, explain the prodromal gastric dysmotility observed in PD patients
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