The role of toll-like receptor-4 in gut-brain cross talk in a murine model of parkinson's disease

Background. Gastrointestinal dysfunction is a common symptom in patients suffering from Parkinson's disease (PD). The intestinal symptoms precede the onset of classical motor symptoms and α-synuclein brain pathology by many years, and their occurrence in otherwise healthy people is associated with an increased risk of developing the disease. The intestine might be an early site reflecting the development of PD. Recently it was found that abnormal intestinal permeability correlated with α-synuclein positive Lewy bodies in the enteric nervous system (ENS). Toll like receptors (TLRs) are expressed by innate immune cells in gut and TLR4 is required for α-synuclein-induced proinflammatory activity of microglial cells in the brain. We hypothesize that intestinal TLR4 dysregulation may play a role in intestinal pathology of PD. Methods. Rotenone is a pesticide that inhibits Complex I of the mitochondrial respiratory chain. Rotenone exposure in rodents is a frequently used model for studying PD since it is able to reproduce PD pathological features found in the brain of PD patients. Male C57BL/6J mice, TLR4 deficient and wild type mice were given rotenone orally (10 mg/kg daily by oral gavage for 28 days) and animals were sacrificed after 28 days. Control mice received vehicle. Rotarod tests were performed on days 5, 10, 15, 21 and 28. Intestinal transit time was assessed 28 days after surgery (N= 10). Results. Rotenone induces motor deficits (disturbed rotarod handling), delayed intestinal transit time and α-synuclein accumulation in the ENS in mice. Moreover, we observed inflammation in the gut in rotenone-treated mice characterized by reduced colon length, an increased number of CD3 positive T cells and neutrophil infiltration. TLR4 deficient mice were partly protected from the development of rotenone-induced motor deficits and delayed intestinal transit time. No effect was observed on colon length reduction after rotenone treatment when comparing TL4 deficient and wild type mice. Conclusions. Oral rotenone caused: 1. PD like motor deficits; 2. α-synuclein pathology in ENS and 3. intestinal motility dysfunction and inflammation. TLR4 seems partly involved in the motor dysfunction and intestinal phenotype found after rotenone administration. Our results support the hypothesis that gut/brain cross talk possibly via TLR4 plays a central role in α-synuclein-induced PD pathology.