Abstract
Patients with Parkinson’s disease often experience non-motor symptoms including constipation, which manifest prior to the onset of debilitating motor signs. Understanding the causes of these non-motor deficits and developing disease modifying therapeutic strategies has the potential to prevent disease progression. Specific neuronal subpopulations were reduced within the myenteric plexus of mice 21 days after intoxication by the intraperitoneal administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and was associated with a reduction in stool frequency, indicative of intestinal dysfunction. Oral administration of the divalent copper complex, CuII(atsm), which has been shown to be neuroprotective and restore motor performance to MPTP lesioned mice, improved stool frequency and was correlated with restoration of neuronal subpopulations in the myenteric plexus of MPTP lesioned mice. Restoration of intestinal function was associated with reduced enteric glial cell reactivity and reduction of markers of inflammation. Therapeutics that have been shown to be neuroprotective in the central nervous system, such as CuII(atsm), therefore also provide symptom relief and are disease modifying in the intestinal tract, suggesting that there is a common cause of Parkinson’s disease pathogenesis in the enteric nervous system and central nervous system.
Highlights
Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by chronic and progressive motor impairment including dyskinesia, rigidity, instability, and tremors[1]
Enteric dopaminergic neurons are predominantly found in the submucosal plexus (SMP) and myenteric plexus (MP) of the upper gastrointestinal tract where the release of dopamine inhibits gut motility[20,21]
To determine whether treatment with CuII(atsm) can attenuate MPTP induced loss of dopaminergic neurons in the enteric nervous system (ENS) of the upper intestine, whole mounts were prepared from the MP of the distal ileum and the number of tyrosine hydroxylase immunoreactivity (TH-IR) neurons were quantified
Summary
Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by chronic and progressive motor impairment including dyskinesia, rigidity, instability, and tremors[1]. While the etiology of idiopathic PD is unclear it is characterized by the presence of Lewy bodies and Lewy neurites, which are primarily composed of α-synuclein, and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc)[2] These pathologies correlate with the subsequent motor disturbances experienced by patients. In addition to classic motor disturbances virtually all PD patients develop some level of autonomic dysfunction, including those affecting the gastrointestinal tract[3]. It is not clear whether gastrointestinal symptoms are the consequence of a loss of extrinsic innervations arising from neuronal loss in the central nervous system (CNS) or a primary consequence of pathogenesis in the enteric nervous system (ENS). Few studies have examined the ENS, those that have show changes in neuronal populations, accumulation of α-synuclein and changes in gastrointestinal function11. α-synuclein has been reported to aggregate in the myenteric neurons of hA53T transgenic mice and propagate from the gut to the brain in rats following injection of human brain extracts containing aggregated α-synuclein suggesting the potential for transmission of synucleinopathy in the ENS8,12
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