Relationship Between Desensitized Nicotinic Acetylcholine Receptors And Parkinson's Disease

Nicotinic acetylcholine receptors (nAChRs) desensitization can be described as a decline or loss in response to agonists after repetitive or chronic exposure to agonists. Traditionally, nAChRs desensitization is viewed as a non-functional state. However, studies from our laboratory have shown that desensitized nAChRs only were not mediating N-like response to agonists; indeed they were not a non-functional state and had specific physiological functions. Evidence from epidemiological studies has revealed a negative association between cigarette smoking and the occurrence of Parkinson's disease (PD). However, nAChRs in brain of smokers are desensitized following chronic or repetitive nicotine stimulation. Therefore, the study of the relationship between desensitized nAChRs and PD is valuable because it can help us to understand the pharmacological basis of the epidemiological finding that cigarette smoking is negatively associated with the occurrence of PD.The accentuation of cholinergic system in PD is different from that of cholinesterase inhibitor poisoning in aspect of pathophysiology and mechanism. In PD, the function of dopaminergic system decreases, causing the relative accentuation of cholinergic system. When cholinesterase inhibitor poisoning occurs, the inhibition of cholinesterase inhibitor activity can induce excessive accumulation of endogenous acetylcholine which can excite central muscarinic and nicotinic receptors, thereby resulting in the accentuation of cholinergic system. Currently, anticholinergic drugs for these two kinds of accentuation of cholinergic system are mainly muscarinic cholinergic antagonists. Our previous findings have shown that potent drugs for cholinesterase inhibitor poisoning must have both muscarinic and nicotinic antagonistic effects. In order to study whether this law exsits in the medication of PD, we examined the antiparkinsonian effects of benthiactzine which are both muscarinic and nicotinic cholinergic antagonist and can potently antagonize cholinesterase inhibitor poisoning.1. Relationship between nAChRs and Parkinson's diseaseThe purpose of this study was to investigate the effects of desensitized nAChRs on rotational behavior in the unilateral 6-OHDA model of PD. When rats were treated with different doses of nicotine, nAChRs were observed in activated, subacute desensitized, acute desensitized and chronic desensitized states. The rotational behavior of the hemiparkinsonian rats was determined when nAChRs were in the activated or different desensitized states. The results showed that hemiparkinsonian rats exhibited no significant changes in apomorphine-induced rotations when brain nAChRs were in an activated state. However, hemiparkinsonian rats displayed a significant reduction in apomorphine-induced rotational behavior when brain nAChRs were in subacute, acute or chronic desensitized states induced by repeated administration of nicotine. These results suggest that desensitized nAChRs can lead to behavioral improvement in the 6-OHDA rat model of PD. When the central nAChRs were blocked by the nAChR antagonist mecamylamine, nicotine could not produce this effect of behavioral recovery. The hemiparkinsonian rats displayed a significant increase in apomorphine-induced rotations when mecamylamine was administered at doses of 0.5, 0.75, and 1.0 mg/kg. These results suggest that when nAChRs were blocked by the nAChR antagonist mecamylamine, the behavior of the hemiparkinsonian rats worsened.In order to identify the mechanisms by which desensitized nAChRs improve the behavior of hemiparkinsonian rats, we examined the effects of desensitized nAChRs on the levels of dopamine (DA) and its metabolites, mRNA expression of dopamine receptor D₁,D₂ and MAO-B in the striatum of 6-OHDA-lesioned rats using high-performance liquid chromatography and reverse transcription-polymerase chain reaction. Furthermore, we observed the pathological changes of substantia nigra pars compacta (SNpc) region in 6-OHDA rat model of PD. The results showed that nAChRs desensitization following repeated nicotine stimulation could reverse significantly the decrease of striatal DA and its metabolites levels and the increase in DA turnover in lesioned side striatum of hemiparkinsonian rats. Dopamine D₁ receptor mRNA expression increased significantly, whereas dopamine D₂ receptor mRNA expression remained unchanged in lesioned side striatum of nicotine-treated rats compared to 6-OHDA-lesioned rats when nAChRs were desensitized. Meanwhile, nicotine-treated rats displayed a significant decrease in MAO-B mRNA expression in lesioned side striatum compared to 6-OHDA-lesioned rats after nAChRs desensitization. The pathological results demonstrated that there was a significant decrease in the amount of hematoxylin and eosin stained neurons in lesioned side SNpc region of 6-OHDA-lesioned rats compared to the SNpc of control rats. However, there is no significant change in the number of hematoxylin and eosin stained neurons and neurons morphology in the lesioned SNpc region between 6-OHDA-lesioned and nicotine-treated lesioned rats when nAChR is desensitized following repeated nicotine stimulation. These results suggest that nAChRs desensitization may lead to behavioral improvement in the 6-OHDA rat model of PD through promoting the levels of DA and its metabolites, inhibiting the increased DA turnover, upregulating dopamine D₁ receptor expression and downregulating MAO-B expression.2. Antiparkinsonian effects of BenthiactzineIn order to investigate the pharmacological characteristics of the accentuation of cholinergic system in PD, we examined the antiparkinsonian effects of benthiactzine which are both muscarinic and nicotinic cholinergic antagonist and can potently antagonize cholinesterase inhibitor poisoning. The results showed that benthiactzine could improve haloperidol-induced parkinsonian symptoms in rats and mice, but it did not have the preponderance over muscarinic cholinergic antagonist atropine. However, benthiactzine could potently antagonize cholinesterase inhibitor poisoning and its antitoxic effects are powerful than that of atropine because it have both muscarinic and nicotinic cholinergic antagonistic effects. These results further confirm that the accentuation of cholinergic system in PD is different from that of cholinesterase inhibitor poisoning in respect of pathophysiology, mechanism, pharmacology and medicine targets. Desenstized nAChRs could alleviate symptoms of PD, but aggravate the toxicity of cholinesterase inhibitor. Blocking nAChRs could antagonize the toxicity of cholinesterase inhibitor, but aggravate symptoms of PD.From these observations, we come to conclusions as follow:1. Desensitized nAChRs can lead to behavioral improvement in the 6-OHDA rat model of PD.2. Desensitized nAChRs is different from blocked nAChRs (by mecamylamine). Desensitized nAChRs improved behavioral impairment in hemiparkinsonian rats, while blocked nAChRs (by mecamylamine) made them worse.3. nAChRs desensitization may lead to behavioral improvement in the 6-OHDA rat model of PD through promoting the levels of DA and its metabolites, inhibiting the increased DA turnover, upregulating dopamine D₁ receptor expression and downregulating MAO-B expression.4. The accentuation of cholinergic system in PD is different from that of cholinesterase inhibitor poisoning in respect of pathophysiology, mechanism, pharmacology and medicine targets. Desenstized nAChRs could alleviate symptoms of PD, but aggravate the toxicity of cholinesterase inhibitor. Blocking nAChRs could antagonize the toxicity of cholinesterase inhibitor, but aggravate symptoms of PD.