Dyskinesia and brain-derived neurotrophic factor levels after long-term levodopa and nicotinic receptor agonist treatments in female mice with near-total unilateral dopaminergic denervation

Abstract

Background: The treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role. Here, female mice with near-total unilateral 6-hydroxydopamine-induced nigrostriatal lesions were chronically treated with levodopa, and the effects of the α7 nicotinic receptor partial agonist AZD0328 and nicotine on LID were assessed. At the end of the experiment, BDNF protein levels in the prefrontal cortex and striatum were measured.

Results: Five-day treatments with three escalating doses of AZD0328 and a 10-week treatment with nicotine failed to alleviate LID. BDNF levels in the lesioned striatum correlated positively with LID severity, but no evidence was found for a levodopa-induced elevation of corticostriatal BDNF in the lesioned hemisphere. The nicotine treatment decreased BDNF levels in the prefrontal cortex but had no effect on striatal BDNF.

Conclusions: The findings suggest that treatment of LID with nicotinic agonists may lose its effectiveness as the disease progresses, represent further evidence for a role for BDNF in LID, and expand previous knowledge on the effects of long-term nicotine treatment on BDNF.

Keywords: Alpha7 nicotinic receptors; BDNF; Levodopa-induced dyskinesia; Nicotine; Parkinson’s disease.

Fig. 1

Timeline of the experiments. Mice were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) injections into the medial forebrain bundle. Levodopa (6 mg/kg) together with benserazide (1.5 mg/kg) was administered s.c. daily (Mon–Fri). The α7 nicotinic receptor partial agonist AZD0328 was administered s.c. at three escalating doses for 1 week (Mon–Fri) per dose. Nicotine was administered continuously in saccharin-sweetened drinking water, with the concentration gradually increased to 300 µg/ml over 2 weeks. Severity of levodopa-induced dyskinesia was assessed from videos recorded weekly at the indicated time points

Fig. 2

Characterization of the near-total unilateral nigrostriatal lesion model. a Representative section, immunostained for tyrosine hydroxylase, showing the ventral midbrain dopaminergic areas, including the substantia nigra pars compacta (SNC), of a study animal lesioned with a 6-hydroxydopamine injection into the medial forebrain bundle. b Tyrosine hydroxylase (TH)-positive immunostaining remaining in the SNC of the study animals at the end of the experiments (n = 10). Less immunostaining remained in animals treated chronically with nicotine. c Dopamine remaining in the dorsal striatum of a separate set of animals, lesioned with identical 6-hydroxydopamine injections, as measured with HPLC (n =5). *Difference to vehicle, P < 0.05, t test

Fig. 3

No effect on levodopa-induced dyskinesia by chronic treatment with nicotinic receptor agonists. Mice were lesioned unilaterally with 6-OHDA, and dyskinesia was pre-induced by 2 weeks of levodopa treatment (6 mg/kg s.c.). a The α7 receptor partial agonist AZD0328 was administered s.c. 30 min before levodopa for 1 week per dose (5 days per week), and dyskinesia severity was assessed from video recordings captured on the fifth day. No statistically significant differences in total dyskinesia severity between treatment groups were found. b After a 1-week washout, chronic levodopa treatment (6 mg/kg) was continued and nicotine treatment in drinking water (up to 300 µg/ml) was initiated. Dyskinesia severity was assessed from weekly video recordings. Nicotine treatment did not reduce but transiently exacerbated dyskinesia severity, with a statistically significant effect on axial dyskinesia (two-way repeated measures ANOVA, treatment × time, P < 0.05). Values represent the mean ± SEM of 6 mice

Fig. 4

Brain-derived neurotrophic factor (BDNF) protein levels in chronically drug-treated lesioned mice. a No interhemispheric differences in BDNF protein levels of the striatum and the prefrontal cortex were found after 15 weeks of levodopa treatment. After 10 weeks of chronic nicotine treatment BDNF levels were reduced in the prefrontal cortex of nicotine-treated animals, with no effect on striatal BDNF. Plots show median, quartiles, range, and distribution (n = 6 per group). **Main effect of treatment P < 0.01, two-way ANOVA. b BDNF levels in the lesioned striatum were positively correlated with dyskinesia severity (r = 0.582, P < 0.05, n = 12)