Abstract
Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.
Highlights
In Parkinson’s disease (PD), the neurodegeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) leads to severe motor deficits linked to profound alterations in the functioning of the cortico-basal ganglia-thalamo-cortical loop circuits [1,2]
We demonstrated that bee venom (BV) treatment efficiently alleviated akinesia-like deficit in both the neuroleptic-induced catalepsy model and in the hemiparkinsonian rat model based on extensive 6-hydroxydopamine (6-OHDA)induced lesion of nigral dopamine neurons
We investigated the cellular substrates of BV action in these models by in vivo electrophysiological recordings of spontaneous and cortically-evoked neuronal discharge patterns in the substantia nigra pars reticulata (SNr) the main basal ganglia output structure in rodents
Summary
In Parkinson’s disease (PD), the neurodegeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNc) leads to severe motor deficits linked to profound alterations in the functioning of the cortico-basal ganglia-thalamo-cortical loop circuits [1,2]. The adverse effects resulting from the long-term dopamine replacement pharmacotherapy using L-DOPA has fostered the research of alternative or adjunctive symptomatic treatments, including pharmacological, surgical and cell- or gene-based therapies [3,4,5,6]. One BV component, is a blocker of small conductance Ca2+activated K+ (KCa2 or SK) channels that have been shown to modulate dopamine neuron survival or phenotype [9,16,17] and are attracting increasing interest for pharmacotherapy [18,19,20]. Confirming the interest of targeting SK channels in PD, apamin has been recently reported to reinstate minimal DA activity in the striatum and alleviate the non-motor symptoms induced by partial DA lesions [21]. Apamin alleviated motor symptoms in extensive dopamine degeneration model [21], suggesting that the effects of SK channel blockade can bypass the dopamine system
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