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

α‐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.


Introduction
The purpose of this paper is to explain the biochemical mechanisms responsible for the symptom of constipation in patients diagnosed with Parkinson's Disease (PD) and Neurocognitive Disorder with Lewy Bodies (NCDLB) patients, and the mechanisms through which Donepezil produces symptom relief.
Compared with other AChEIs, including Galantamine and Rivastigmine, the cholinergic agonist Donepezil has performed favorably for treating cognitive impairment in patients with PD and NCDLB, improving cognition, but with fewer side effects [73,74].Donepezil has been shown to produce significant improvements in cognition and behavior which disappeared when Donepezil was withdrawn, but treatment gains were restored on recommencement of Donepezil [75].Donepezil has been shown to improve cognition for up to 52 weeks in longterm treatment of NCDLB patients, without increasing the risk of Parkinsonian features or other clinically significant safety events [76,77].Donepezil has also been shown to reduce Lewy pathology cholinergic impairment including hallucinations and delusions and psychotic symptoms in PD patients, without apparent side effects or exacerbation of Parkinsonian symptoms [78][79].Although an early study suggested that treatment of NCDLB with Donepezil was sometimes associated with an increase in Parkinsonian features, a Cochrane database systematic review of previous research using cholinergic agonists to treat PD & NCDLB found that Donepezil produced consistent reduction in neurocognitive symptoms without exacerbation of Parkinsonian features or other side effects [87,88].These findings have been reproduced in subsequent research [89,90].
More specific to ENS Lewy pathology and impairment, Donepezil has been shown to reduce ANS symptoms including constipation in nongeriatric affective patients, and increase cholinergically mediated bowel contractions as much as 477% in patients suffering from severe intestinal dysmotility [91,92].

Symptom Treatment of Cholinergic Lewy Pathology in the ENS
Despite its prevalence in Lewy Body patients [46,47] and debilitating impact on quality of life, gastric immotility is rarely a focus of treatment for patients with PD and NCDLB [4,34,36,39,[53][54][55][56].When PD and NCDLB constipation is addressed, primary care physicians typically recommend conventional (often over-the-counter) treatments, despite data demonstrating that such treatments are ineffective with this population [54].
Based on researchdemonstrating Donepezil's efficacy in treating cholinergic impairment in patients with PD and NCDLB, and its effectiveness in reducing constipation and increasing bowel motility in non geriatric patients [73][74][75][76][77][78][79][88][89][90]93,94].Donepezil has been used specifically to treatconstipation in PD and NCDLB patients, with consequent significant reduction of the symptom of constipation, without exacerbation or instigation of other symptoms [39].A follow up study indicated that the progression of Lewy body pathology had advanced in some patients, leading to exacerbation of CNS and ANS symptoms including blunted affect, dysphoric mood, generalized anxiety, sleep disturbance (onset, median and terminal waking, REM sleep behavior disorder or RSBD and/or REM sleep without atonia, or RSWA), cognitive interference (short-term memory loss and difficulty with wordfinding), passive suicidal ideation, appetite suppression, and exacerbation of Parkinsonian features (motor retardation, joint and muscle pain, reduced range of motion, diminished strength and coordination, increased tremor, gait disturbances, and difficulties with balance).However, there was no exacerbation of the symptom of constipation, nor emergence of new symptoms in any of the patients in the study, suggesting that Donepezil might have long-term benefit for mitigating cholinergic Lewy pathology in the ENS of patients with PD and NCDLB [40].

The Mechanism of Symptom Relief for Cholinergic Lewy Pathology in the ENS
The observed benefit of using Donepezil to reduce the symptom of constipation in PD and NCDLB patients bears some explanation.Specifically, what are the biochemical mechanisms responsible for the symptom of constipation, and through what mechanisms does Donepezil induce symptom relief?Because 95% of Myenteric Plexus (MP) innervation is cholinergic, Lewy Body pathology in the MP manifests primarily as α-synuclein protein aggregation in the cholinergic neurons of the MP and the CSMP [8,[14][15][16][17][18][19][20][21].In the MP and CSMP, αsynuclein pathology does not appear exclusively in the form of large Lewy bodies near the nucleus.Small Lewy bodies and other proteins aggregate even more abundantly in neurites (axons and dendrites) [33].
The specific biochemical mechanisms posited for α-synuclein pathology-based reduction of cholinergic functioning include endoplasmic reticulum (ER) stress, blockage in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking, and mitochondrial dysfunction, all of which contribute to α-synuclein-induced cell death [93,94].The degeneration of cholinergic neurons leads to a decline in the level of acetylcholine (ACh) [95].
The mechanisms through which Donepezil mitigates these symptoms is twofold.AChEIs like Donepezil inhibit the action of the ACh-hydrolyzing enzyme acetylcholinesterase (AChE), increasing ACh levels, with consequent reduction in symptoms associated with progressive cholinergic dysfunction [95].Donepezil is a specific, reversible AChEinhibitor [96,97].Donepezil also interacts independently with neuronal nicotinic ACh receptors [98].Donepezil's dual action has made it a longstanding choice for countering cholinergic impairment [74,95,98].Donepezil's successful employment in the treatment of constipation in case studies of patients with PD and NCDLB, as well as its demonstrated efficacy in reducing constipation in PD and NCDLB patients using Carbidopa-Levodopa, suggests that the mechanism of boostingACh levels in the MP and CSMP restores motility to the bowel, significantly reducing constipation without increasing Parkinsonian features or other clinically significant symptoms [39,40].

Discussion and Conclusions
As with the use of any medication, Donepezil's potential for symptom reduction has to be weighed against its potential side effects.These can include diarrhea, loss of appetite, muscle cramps, nausea, trouble in sleeping, unusual tiredness or weakness, and vomiting, with less common side effects including abnormal dreams, constipation, dizziness, drowsiness, fainting, frequent urination, headache, joint pain, stiffness, or swelling, mental depression, pain, unusual bleeding or bruising, and weight loss (Pfizer US Pharmaceuticals, 2016).AChEIs including Donepezil also have the potential for rare but potentially dangerous side effects, including muscle breakdown (rhabdomyolysis) and a neurological disorder called neuroleptic malignant syndrome (NMS) [80][81][82][83][84][85][86].Donepezil has demonstrated efficacy in mitigating Lewy body impairment of the cholinergic pathways in the MP and CSMP of patients diagnosed with PD and NCDLB, increasing bowel motility and reducing the symptom of constipation, without exacerbating or instigating other symptoms [39,40].One possible conclusion is that the use of the AChEI Donepezil compensates at least in part for Lewy body impairment of cholinergic pathways in the MP and CSMP, reducing the symptom of constipation in patients with PD and NCDLB.
In case studies, the use of Donepezilwas also associated with significant reductions in constipation and the resumption of daily bowel movements in patients using Carbidopa-Levodopa.Another possible conclusion is that Donepezil mitigates constipation in Lewy body patients receiving prescriptive Carbidopa-Levodopa.
The strength of these conclusions is limited by our current understanding of Lewy pathology, its etiology, and progression.Although these early findings suggest that Donepezil might be effective in reducing constipation in patients with PD and NCDLB through a mechanism that directly addresses Lewy body cholinergic impairment in the MP and CSMP, further research is necessary using larger numbers of subjects matched for diagnosis, age, gender, and other variables.