oxadiazoles and Parkinsonian-Disorders

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Catechol O-Methyltransferase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Erythrocytes; Female; Levodopa; Locomotion; Macaca fascicularis; Oxadiazoles; Parkinsonian Disorders; Time Factors

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4β2 receptors being the most abundant heteromer. The stoichiometry of α4β2 receptors can be either (α4)(3)(β2)(2) or (α4)(2)(β2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4β2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4β2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4β2 nAChR in rotational and analgesic responses and confirm striatal α4β2 receptors to be of the HS form.

Topics: Allosteric Regulation; Animals; Azepines; Corpus Striatum; Female; Male; Nicotinic Agonists; Oxadiazoles; Oxidopamine; Pain; Pain Measurement; Parkinsonian Disorders; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Nicotinic; Rotation

There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinson's disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD.. The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP.. We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP.. Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD.

Topics: Animals; Basal Ganglia; Corpus Striatum; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Male; Mice; Mice, Inbred C57BL; Oxadiazoles; Parkinsonian Disorders; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase