Mechanisms of α‐Synuclein Pathology and Treatment in the Enteric Nervous System

Abstract

Abstractα-synuclein (Lewy Body) pathology is commonly found in the enteric nervous system (ENS) of patients diagnosed with Neurocognitive Disorder with Lewy Bodies (NCDLB) and Parkinson's Disease (PD). Lewy pathology in the ENS can produce symptoms of bowel immotility, including constipation, obstipation, and bowel impaction. These symptoms significantly reduce the quality of life for the patient, producing hardship for the patient and care providers. In Lewy body patients, medical intervention using acetylcholinesterase inhibitors (AChEIs) can significantly reduce or alleviate bowel immotility. The specific mechanism through which the cholinergic agonist Donepezil mitigates Lewy Body bowel immotility is explained. Practice, 1143 Deer Trail Lane, Solvang, California 93463, USA, Tel: 805-688-1229 Fax: 805-686-9382; E-mail: clepkowsky@gmail.com of α-synuclein aggregates in the MP predates cognitive and motor functional manifestations of Lewy body diseases so consistently that it has been nominated as a potential biomarker for Lewy pathology [10,17,30]. Symptomatic Manifestations of Cholinergic Lewy Pathology in the ENSLewy body cholinergic impairment in the ENS manifests symptomatically as gastric immotility and constipation [13,[31][32][33][34][35][36][37][38][39][40][41]. Increased colonic transit time and impaired gastric emptying are frequently found in PD patients [35,42]. The prevalence of constipation in PD is at least three times that of the general population, leading some researchersto suggest that constipation might be a universal feature of PD [47,48]. Bowel immotility can occur 20 years before diagnosis of PD or NCDLB, suggesting that it might be a prodromal symptom for both disorders [5,19,36,44,[49][50][51][52].As α-synuclein pathology advances in the ENS, symptoms of gastric immotility advance from constipation to obstipation and impaction. Escalating gastric immotility in PD and NCDLB can interfere with mobility, sleep, cognition, and mood, increasing the cost of care, and potentially debilitating and/or dramatically reducing the quality of life for patients. [4,34,36,[53][54][55][56] Potential Exacerbation of ENS Symptoms by AntiParkinson MedicationLPD and NCDLB patients with significant Parkinsonian motoric/gait features are often prescribed L-dopa agents like Carbidopa-Levodopa (known also by the brand names Sinemet and Stalevo) in order to preserve gait, balance, and other basic motor functions [40,57,58]. Carbidopa-Levodopa's potential side effects include constipation [59]. which can complicate or exacerbate gastric immotility due to ENS Lewy pathology. Medications frequently used for the treatment of resting tremor in PD and NCDLB includeTrihexyphenidyl (marketed as Artane or Trihex) and Benztropinemesylate (marketed as Cogentin), identified as definite anticholinergics that can also exacerbate gastric immotility through suppression of the cholinergic neurotransmitter pathways innervating the ENS [58,[60][61][62].