Constipation and motility dysfunction are the most common non-motor gastrointestinal (GI) symptoms in Parkinson's disease (PD) patients [1]. Transient receptor potential vanilloid-type 4 (TRPV4) are expressed in the intestine and can control GI motility [2]. But the specific role of this channels in PD remains largely unknown.
The aim of the study was to test the action of transient receptor potential vanilloid-type 4 selective agonist GSK1016790A on smooth muscle cells contraction in rat's colon with experimental Parkinson's disease.
The PD was induced by single unilateral stereotaxic injection of 12 µg 6-OHDA. The percentage of destroyed dopaminergic neurons was evaluated in apomorphine test (0.5 mg/kg, i.p.) at 1 and 2 weeks after surgery. The water content in faeces was evaluated on the 1st day, then at the 3rd week and 7th month of the experiment. The daily volume of water consumption and GI transit time were evaluated at the 3rd week and 7th month after surgery. The expression of TRPV4 channels was evaluated by qRT-PCR in muscles and mucosal layer of colon. The action of TRPV4 agonist GSK1016790A (0.3 mmol) on smooth muscle cells of colon was estimated by isometric tension recording.
The apomorphine test showed a progressive increase in the number of turns between the 1st and 2nd week after inducing 6-OHDA-PD. The water content in faeces was increased at the 3rd week (P<0.05) vs. 1st day of the experiment. The rats with 6-OHDA-PD drank less water vs. placebo and intact groups. We observed a 17% delayed GI transit time in 6-OHDA-PD rats (P<0.01) vs. intact and 21% vs. sham-lesioned group of rats 3 weeks after the 6-OHDA treatment. 7 months after the surgery GI transit time was increased more than twice in all studied groups. In 6-OHDA rats, we observed changes in TRPV4 mRNA levels, 50 fold decrease in muscle layer and 2,3-fold increase in mucosa vs sham lesioned rats. TRPV4 agonist action on smooth muscle cells of 6-OHDA-PD rats was reduced by 21% compared to intact group and by 46% in sham-lesioned group (P<0.05).
Pharmacological activation of TRPV4 ion channels by their selective agonist GSK1016790A decreased the contractile activity of colon smooth muscle cells in 6-OHDA rats' model of Parkinson's disease.