Effects of L-DOPA/Benserazide Co-Treatment on the Patterns of Colonic Neuromuscular Excitatory Cholinergic and Tachykininergic Pathways in the Presence of Experimental Parkinson's Disease

Introduction. Patients with Parkinson's disease (PD) can develop digestive motor dysfunctions associated with changes in enteric nervous system. The mainstay therapy for PD is represented by levodopa (L-DOPA) plus DOPA-decarboxylase inhibitors. However, the possible effects of these drugs on intestinal motility in PD are unclear. This study examines the effects of L-DOPA plus benserazide (BE) on colonic neuromuscular excitatory pathways in rats with experimental PD. Methods. PD was induced in male rats by intra-nigral injection of 6- hydroxydopamine (6-OHDA). Animals injected with 6-OHDA vehicle served as normal controls (sham-PD). PD or sham-PD animals were treated orally with L-DOPA/BE (6/15 mg/ Kg/day) or their vehicle for 28 days, starting 28 days after intra-nigral injection. At the end of drug treatment, colonic longitudinal muscle preparations were isolated, set up in organ baths, and connected to isometric transducers to record neurogenic contractions (g/g tissue) elicited by electrical stimulation (ES, 1-20 Hz) under the following conditions: 1) Krebs solution containing guanethidine (10 μM), Nω-nitro-L-arginine methylester (L-NAME, 100 μM) and L-732,138 (NK1 receptor antagonist, 10 μM) to record cholinergic contractile responses; 2) Krebs solution containing L-NAME, guanethidine and atropine (1 μM) to obtain contractions driven primarily by tachykinins. Myogenic contractions elicited by carbachol (1 μM) or exogenous substance P (SP, 0.1 μM) in the presence of tetrodotoxin (1 μM) were also recorded. Results. In sham-PD animals, treatment with L-DOPA/BE did not modify all the patterns of stimulated motor activity, in comparison with drug vehicle treatment. When compared with sham-PD rats, PD animals displayed the following colonic motor alterations: 1) a reduction of atropine-sensitive neurogenic cholinergic contractions evoked by ES (10 Hz) (-24±2.3%); 2) an increase in myogenic contractions evoked by carbachol (+93±13%); 3) an enhancement of electrically evoked (10 Hz) neurogenic L-732,138-sensitive tachykininergic motor responses (+70±4%); 4) a potentiation of myogenic contractions elicited by exogenous SP (+113±7.6%). In PD animals, treatment with L-DOPA/BE was associated with a restoration of ES-evoked neurogenic cholinergic motor responses, while the changes in carbachol-evoked myogenic contractions were unaffected. On the other hand, treatment of PD animals with L-DOPA/BE did not produce any effect on the alterations of both ES- and SP-evoked tachykininergic motor responses. Conclusion. In experimental PD, treatment with L-DOPA/BE resulted in a recovery of colonic cholinergic excitatory neurogenic motility, suggesting a protective effect of L-DOPA/BE on the alterations of cholinergic neurotransmission associated with experimental PD.