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.
Highlights
Hallmark lesions of Parkinson’s disease (PD) were traditionally considered to be present in the dopaminergic neurons of the substantia nigra (SN) and in the noradrenergic neurons of the locus coeruleus (LC)
Our results show that rotenone induces region- and exposure time-dependent changes in the concentration-response curves for carbachol and dopamine
In order to analyze the effect of rotenone on the enteric neurons of rotenone-exposed mice, we studied the expression of different neuronal subpopulation markers present in the duodenum, jejunum, ileum, and colon from vehicle- and rotenone-exposed mice
Summary
Hallmark lesions of Parkinson’s disease (PD) were traditionally considered to be present in the dopaminergic neurons of the substantia nigra (SN) and in the noradrenergic neurons of the locus coeruleus (LC). Pathological studies showed that PD patients typically have lesions in other central nervous system (CNS) and PNS structures (e.g., the ENS, the sympathetic coeliac ganglion (CG), the intermediolateral nucleus (IML) of the spinal cord, the motor nucleus of the vagus DMV or the amygdala) [1, 2]. Based on autopsies performed on PD patients and healthy individuals, Braak et al proposed a pathological staging of the disease [5] According to this staging, PD lesions follow a spatio-temporal pattern that starts in the olfactory bulb (OB) and the ENS progressing into the CNS through synaptically connected structures. This pathological staging of the disease seems to correlate well with the appearance of early non-motor symptoms in PD patients including hyposmia, gastrointestinal alterations, autonomic dysfunction, and pain [6]
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