The Role Of Brain Histamine In The Pathogenesis Of Parkinson' Disease

So far the etiology of PD and the underlying mechanism responsible for the degeneration of dopaminergic neurons still remain unclear.In PD patients,the disturbance of many neurotransmissions might contribute to the pathological processes of PD.Histamine,as a neurotransmitter,has gained more and more attention in PD.It seems that the brain histaminergic system has been activated in PD. However,it is still unclear what the exact role and mechanism of increased histamine is in PD.Partâ… :Involvement of brain endogenous histamine in the degeneration of dopaminergic neurons in 6-hydroxydopamine-lesioned ratsAim:To determine the role of endogenous histamine in the degeneration of dopaminergic neurons in the substantia nigra pars compact(SNpc),Methods:This issue was investigated by changing the brain histamine levels by giving histaminergic agents,and administered histamine receptor antagonists in the PD animal model,i.e. the 6-hydroxydopamine(6-OHDA)-lesioned rat.On day 1,7 and 14 after 6-OHDA lesion,apomorphine-induced turning behavior was tested and some of animals were used for Tyrosine hydroxylase(TH)immunohistochemisry.Results:In saline-treated animals,6-OHDA infusion produced a progressive increase in apomorphine-induced turning rate and a loss of tyrosine hydroxylase immunoreactive(TH-ir)neurons in the SNpc.Histaminergic agents were given prior and daily for 1,7 or 14 days after 6-OHDA infusion.Histidine(500 mg/kg,i.p.),a precursor of histamine,increased the turning rate(27%on day 7 and 26%on day 14,respectively;p＜0.05)and also the loss of TH-ir neurons,but only on day 1 and 7(67%vs 47%and 90.4%vs 74%loss, respectively;p＜0.05).In contrast,α-fluoromethylhistidine(α-FMH,25μg,i.c.v.), an irreversible inhibitor of histidine decarboxylase(HDC),significantly decreased the turning rate(25%on day 7 and 26%on day 14,respectively;p＜0.05)and prevented the loss of TH-ir neurons,also only on dayl and day 7(28%vs 47%and 58%vs 74% loss,respectively;p＜0.05).In addition,the histamine H-1 receptor antagonist pyrilamine(5μg,i.c.v.),but not the H₂ receptor antagonist cimetidine(5μg,i.c.v.), also decreased the turning rate(38%on day 7 and 21%on day 14,respectively;p＜0.05)and prevented the loss of TH-ir neurons on dayl and day 7(38%vs 51%and 60%vs 78%loss,respectively;p＜0.05).On day 14 after 6-OHDA lesion,there were no significant differences in the number of TH-ir neurons among all the different treatment groups.Conlusion:These findings indicate that endogenous histamine may accelerate the degeneration of dopaminergic neurons via its H₁ receptor,while attenuation of histamine transmission may play a protective role on it in the early stage of development of 6-OHDA lesioned PD rats.Partâ…¡:Modification of apomorphine-induced turning behaviour by histaminergic ligands in 6-hydroxydopamine-lesioned ratsAim:To determine the role of histamine and its receptors in the neural circuit of basal ganglia,apomorphine-induced turning behavior was used to assess the function of the basal ganglia.Methods:Unilaterally lesioned rats were given histaminergic agents, and then apomorphine-induced turning behavior was tested twice,on day 7 and 14 after 6-OHDA infusion,respectively.Results:Compared with saline-treated rats, histidine(500mg/kg,i.p.)a precursor of histamine,increased the turning rate(P＜0.05),while a-fluoromethylhistidine(α-FMH,25μg,i.c.v.),an irreversible inhibitor of histidine decarboxylase(HDC),decreased it(P＜0.05)only on day 14 after 6-OHDA infusion.Both the histamine H₁ receptor antagonist pyrilamine(10 and 50μg,i.c.v.)and the H₂ receptor antagonist cimetidine(10 and 50μg,i.c.v.)significantly decreased the turning rate not only on day 7 but also day 14 after 6-OHDA infusion. In addition,the histamine H₃ receptor agonist immepip(10μg,i.c.v.)also decreased the turning rate(P＜0.05)only on day 14 after 6-OHDA infusion.Conclusion:The present findings indicate that histamine may modify the synaptic output of the basal ganglia in a complex way via their H₁,H₂ and H₃ receptors. Partâ…¢:Histidine decarboxylase mRNA expression in the human hypothalamic tuberomammillary nucleus in Parkinson's diseaseAim:To determine whether the increase of histaminergic system in PD is due to the increased synthesis,Methods:Using in situ hybridization we determined the amount of histidine decarboxylase(HDC)mRNA in the tuberomammillary nucleus(TMN)in post mortem brain tussue of 11 PD subjects and 11 controls.Results:In control group, the amount ofHDC mRNA was 6821±863 a.u.(n=11).The amount of HDC mRNA in PD group was a little lower(6250±608 a.u.,n=11)than that of controls,but no significant difference was found beteween control and PD groups(p = 0.37).Conclusions:The increase of histaminergic system in PD is not due to the increased synthesis,there might be some unknown mechanisms involved in the increased histamine in PD.