Dietary Serine Prevents Synergistic Action of Paraquat and Lectins in the Development of Parkinsonian‐like Gastric Dysmotility

Parkinson's disease (PD) involves degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and is characterized by motor and non‐motor symptoms, including gastrointestinal (GI) dysmotility. In recent years a novel theory hypothesizes that idiopathic PD could be triggered by the absorption of environmental pathogens in the GI tract. Their retrograde, vagally‐mediated transport to the central nervous system, possibly occurs via a recently discovered nigro‐vagal pathway, and ultimately induces the degeneration of SNpc neurons. We have shown previously that ingestion of high doses of lectins (0.2%) reduce gastric motility in a manner reminiscent of the gastric dysfunctions observed in PD patients, thus suggesting that either lectins may themselves be the environmental pathogen or by virtue of their membrane permeability, lectins may act as chaperones to facilitate the transport to the CNS of toxins known to cause PD. One of these toxins is the herbicide paraquat, which, when administered at high doses (up to 100mg/kg), induces degeneration of dopaminergic neurons and PD‐like motor symptoms. The aim of the present study was to test the hypotheses that: 1) gastric administration of subthreshold doses of lectins and paraquat induce gastric dysmotilty, via actions to compromise SNpc‐vagus‐stomach pathway; and, 2) dietary supplementation with serine prevents or attenuates the development of PD‐like gastric dysfunctions. Four Sprague Dawley rat groups (n=3 each) were gavaged for 7 days with 200μl of i) 1% sucrose (control); ii) 0.05% lectin from Pisum Sativum (L); iii) L + paraquat, 1 mg/kg (1P+L); iv) 1P+L fed with serine enriched diet. Gastric motility and tone were measured 2 weeks post‐gavage via strain gauges sewn to the anterior corpus and antrum surface. Modulation of gastric activity was assessed by microinjections of NMDA in the SNpc (nigro‐vagal pathway) or by microinjections of thyrotropin‐releasing‐hormone (TRH) in the DVC (vagal efferent pathway) or by i.v. bethanechol (direct action on smooth muscle). At the end of the experiment, rats were perfused‐fixed and the brain tissues were collected for α‐synuclein (i.e. hallmark of PD pathology) immunohistochemistry. Our data indicated a decrease gastric response upon stimulation of nigro‐vagal and vagal efferent pathways in the 1P+L group. The impaired response was attenuated by dietary serine treatment. Representative data are summarized in the table below. The response to bethanechol was similar in all groups, indicating that the treatments did not affect the gastric smooth muscle. Misfolded α‐synuclein was detected in DVC of 1P+L group and it was decreased significantly by dietary serine (1P+L+S). Our data suggested that 1) gastric administration of subthreshold doses of lectins and paraquat induce gastric dysmotilty; and, 2) dietary supplementation with serine prevents or attenuates the development of PD‐like gastric dysfunctions. Support or Funding Information NIH DK 55530NMDA TRHAntrum Corpus Antrum Corpustone (mg) motility (% of baseline) tone (mg) motility (% of baseline) tone (mg) motility (% of baseline) tone (mg) motility (% of baseline)control 757.3±173.4 678.9±139.3 362.2±43.02 713.6±172 765.3±309.5 516.9±114.5 362.4±47.4 542.4±92.10L 772.3±353.5 540.9±313.7 433.1±126.1 409.2±75.72 1372±111.5 458±187.04 327±9.1 433.3±181.61P+L 301±79.72 248.3±68.34 269.2±71.91 392.3±100 329.9±128.1 256.7±43.35 252.7±39.6 264.1±50.451P+L+S 895.7±205.1 535.5±127 459.8±44.19 591±145.6 698.1±153.9 622.5±255.6 273.6±88.5 386±32.20