Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease

Abstract

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

Probiotic Enhancement of Antioxidant Capacity and Alterations of Gut Microbiota Composition in 6-Hydroxydopamin-Induced Parkinson’s Disease Rats

“…Risk factors, such as gene mutations (α-syn, parkin), brain injury, stress, and pesticide exposure, are also linked to PD [ 7 ]. Although the origin of PD is not fully understood, recent studies showed that the non-motor symptoms—particularly GI dysfunction—manifest before the premotor phase of PD and may contribute to PD pathogenesis via the gut–brain axis [ 8 , 9 ].…”

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

“…This animal model also showed at least one non-motor symptom associated with PD (i.e. constipation), which was related to the loss of sympathetic and parasympathetic innervation of the intestinal tract 13,14 .…”

“…The prevalence of non-motor symptoms is as a whole equally consistent, however there is a high variability and inconsistency regarding the type of non-motor symptoms that PD-patients present and the type of neurons responsible for each symptom. For example, the prevalence of constipation is of 46.5% (range: 27.5–71.7%) for which alterations in cholinergic and sympathetic neurons as well as enteric neurons has been described 13 , 14 , 38 . In the case of the REM sleep behaviour disorder (RBD) the prevalence is of 34.2% with (range: 29.6–38.7%) and current research suggests that neuronal degeneration of brainstem nuclei, including the pontine tegmental area and medulla, is the pathophysiological cornerstone of RBD 7 , 39 .…”

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

“…The prevalence of non-motor symptoms is as a whole equally consistent, however there is a high variability and inconsistency regarding the type of non-motor symptoms that PD-patients present and the type of neurons responsible for each symptom. For example, the prevalence of constipation is of 46.5% (range: 27.5–71.7%) for which alterations in cholinergic and sympathetic neurons as well as enteric neurons has been described [13, 14, 46]. In the case of the REM sleep behaviour disorder (RBD) the prevalence is of 34.2% with (range: 29.6–38.7%) and current research suggests that neuronal degeneration of brainstem nuclei, including the pontine tegmental area and medulla, is the pathophysiological cornerstone of RBD [7, 47].…”

“…This animal model also shows at least one non-motor symptom associated with PD (i.e. constipation), which was related to the loss of sympathetic and parasympathetic innervation of the intestinal tract [13, 14].…”