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. 2015 Jan:263:277-84.
doi: 10.1016/j.expneurol.2014.09.015. Epub 2014 Sep 28.

The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions

Tanuja Bordia  1 , Matthew McGregor  1 , Roger L Papke  2 , Michael W Decker  3 , J Michael McIntosh  4 , Maryka Quik  5
Affiliations

The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions

Tanuja Bordia et al. Exp Neurol. 2015 Jan.

Abstract

The finding that smoking is inversely correlated with Parkinson's disease and that nicotine attenuates nigrostriatal damage in Parkinsonian animals supports the idea that nicotine may be neuroprotective. Nicotine is thought to exert this effect by acting at nicotinic receptors (nAChRs), including the α7 subtype. The objective of this study was twofold: first, to test the protective potential of ABT-107, an agonist with high selectivity for α7 nAChRs; and second, to investigate its cellular mechanism of action. Rats were implanted with minipumps containing ABT-107 (0.25mg/kg/d). In addition, we tested the effect of nicotine (1mg/kg/d) as a positive control, and also DMXB (2mg/kg/d) which acts primarily with α7 but also α4β2* nAChRs. Two weeks after minipump placement, the rats were lesioned by unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Lesioning alone decreased contralateral forelimb use and adjusted stepping, two measures of Parkinsonism. ABT-107 and nicotine treatment significantly improved these behaviors at all weeks tested, with variable improvement with DMXB. We next investigated the cellular mechanism involved. The striatal dopamine transporter (DAT), a marker of dopaminergic integrity, was reduced ~70% with lesioning. ABT-107 or nicotine treatment significantly increased DAT levels in lesioned striatum; these drugs did not alter DAT levels in intact striatum. ABT-107 and nicotine also significantly improved basal dopamine release from lesioned striatum, as well as nicotine-stimulated dopamine release mediated via α4β2* and α6β2* nAChRs. These data suggest that α7 nAChR agonists may improve motor behaviors associated with nigrostriatal damage by enhancing striatal dopaminergic function.

Keywords: ABT-107; DMXB; Neuroprotection; Nicotine; Nicotinic receptors; Parkinson's disease.

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Conflict of interest statement

Relevant conflict of interest.

ABT-107 is an AbbVie compound; MWD is employed by and owns shares of AbbVie. There are no conflicts of interest for the other authors.

Figures

Fig. 1
Fig. 1
NAChR agonist treatment timeline of 6-OHDA-lesioned rats. Rats were pretreated with vehicle or nAChR agonists via an osmotic minipump and lesioned 2 wk later as detailed in Materials and Methods. The forepaw placement and adjusted stepping test were done 2 to 8 wk after lesioning to determine the extent of motor deficits.
Fig. 2
Fig. 2
α7 nAChR agonist treatment improves forepaw placement in lesioned rats. Rats pretreated with vehicle or nAChR agonists via an osmotic minipump were rendered parkinsonian by unilateral 6-OHDA treatment. Two to 8 wk post-lesion, rats were tested for deficits in the use of their contralateral limb using the forepaw placement or cylinder test. Top panel, the effect of nicotine (1 mg/kg/d) (Study 1). Bottom panel, effect of the α7 nAChR agonists ABT-107 (0.25 mg/kg/d) and DMXB (2 mg/kg/d) (Study 2). Values are the mean ± SEM of 12–25 rats per group. Significance of difference from the vehicle-treated group, *p < 0.5; **p < 0.01; ***p < 0.001.
Fig. 3
Fig. 3
α7 nAChR agonist treatment improves contralateral forepaw use in the adjusted stepping test in lesioned rats. Rats treated with vehicle or a nAChR agonist via minipump were rendered parkinsonian by unilateral injection of 6-OHDA. Two to 8 wk post-lesion, they were tested for postural instability using the adjusted stepping test. The number of forehand adjustment steps made by each forelimb as the animal was moved laterally across the table top was counted. Top panel, the effect of nicotine (1 mg/kg/d) (Study 1). Bottom panel, effect of α7 nAChR agonists ABT-107 (0.25 mg/kg/d) and DMXB (2 mg/kg/d) (Study 2). Values are the mean ± SEM of 12–25 rats per group. Significance of difference from the vehicle-treated group, *p < 0.5; **p < 0.01; ***p < 0.001.
Fig. 4
Fig. 4
α7 nAChR agonist treatment improves the 6-OHDA-induced loss in DAT levels. Rats were administered vehicle or nAChR agonist via minipump and lesioned using 6-OHDA, as described. (A) DAT was measured in the intact and lesioned striatum using 125I-RTI-121 autoradiography. Quantitative analysis (B) shows that 6-OHDA lesioning led to ~70% loss in DAT levels in the lesioned striatum of vehicle-treated rats. However, DAT levels in the agonisttreated group were significantly higher in the lesioned but not intact striatum. Values are the mean ± SEM of 12–25 rats per group. Significance of difference from the vehicle-treated intact side, ***p < 0.001; from vehicle-treated lesioned side, #p < 0.05, ##p < 0.01 using two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 5
Fig. 5
Nicotine prevents the 6-OHDA-induced loss in striatal nAChR-evoked dopamine release. Rats were administered vehicle or nicotine via minipump and lesioned using 6-OHDA. Synaptosomal nicotine-evoked 3H-dopamine release was determined in response to 1 and 10 µM nicotine in intact and lesioned striatum. Release was done in the absence (total nAChR-mediated release) and presence of 50 nM α-CtxMII (α4β2* nAChR-mediated release) with the difference in release defined as α6β2* nAChR-mediated release. Values are the mean ± SEM of 22–25 rats per group. Significance of difference from the vehicle-treated intact side, ***p < 0.001; from vehicle-treated lesioned side, #p < 0.05, ###p < 0.001 using two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 6
Fig. 6
α7 nAChR agonists reduce the 6-OHDA-induced loss in basal dopamine release in striatum. Rats were administered vehicle or nAChR agonist via minipump and lesioned using 6-OHDA. Basal 3H-dopamine release was measured from synaptosomes prepared from intact and lesioned striatum. Values are the mean ± SEM of 12–25 rats per group. Significance of difference from the vehicle-treated intact side, *p < 0.05, ***p < 0.001; from the vehicle-treated lesioned side, #p < 0.05 using two-way ANOVA followed by a Bonferroni post hoc test.
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