Treatment with α 2-adrenoceptor antagonist, 2-methoxy idazoxan, protects 6-hydroxydopamine-induced Parkinsonian symptoms in rats: neurochemical and behavioral evidence

Abstract

Noradrenaline, not only functions as a synaptic transmitter, but also promotes neural differentiation and regenerative processes. In Parkinson’s disease, besides the dopaminergic degeneration, noradrenergic neurons of locus coeruleus origin degenerate as well. Drugs enhancing noradrenergic transmission in the locus coeruleus (e.g. α 2-adrenoceptor antagonists) have been shown to be neuroprotective against Huntington’s and ischemic animal models. However, in Parkinsonian animal models, most of the studies evaluated the worsening of experimental nigral neurodegeneration after locus coeruleus lesions. Here, it has been tested, whether treatment with the selective α 2-adrenoceptor antagonist, 2-methoxy idazoxan (2.5 mg/kg i.p., twice daily for 5 days), before an experimental lesion to nigra, protects dopaminergic neurodegeneration. Dopaminergic degeneration was produced by 6-hydroxydopamine lesion in the median forebrain bundle. The concentrations of dopamine, 5-hydroxytryptamine and its metabolites were analysed in the various regions of the basal ganglia. The concentrations of noradrenaline and dopamine were measured in the regions innervated by locus coeruleus neurons and in the basal ganglia respectively, after 2-methoxy idazoxan treatment. The Parkinsonian behavior was assessed by catalepsy and activity test. 2-Methoxy idazoxan specifically increased the concentration of noradrenaline in the brain regions, innervated by locus coeruleus neurons. 6-OHDA lesion strongly depleted the concentration of dopamine and its metabolites in the striatum and SN, producing catalepsy and hypoactivity. Multiple treatments with 2-methoxy idazoxan reduced some of the observed neurochemical and behavioral indices of 6-hydroxydopamine-induced Parkinsonism, indicating neuroprotection. Although the mechanism underlying the neuroprotective property remains elusive, the therapeutic usage of α 2-antagonists might be helpful in slowing the neuronal death and progression of Parkinson’s disease.