The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease

OBJECTIVES: The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. MATERIALS AND METHODS: A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. RESULTS: No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). CONCLUSION: The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.     

MDL 72,974: a potent and selective enzyme-activated irreversible inhibitor of monoamine oxidase type B with potential for use in Parkinson's disease

Summary MDL 72,974, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine, was designed to be a selective inhibitor of monoamine oxidase type B (MAO-B). In vitro, the compound inhibits rat brain mitochondrial MAO in a concentration and time-dependent fashion and shows marked selectivity for the B form (IC₅₀=680 and 3.6nM for MAO-A and MAO-B, respectively). After oral administration to rats, the compound shows preferential inhibition of brain MAO-B with ED₅₀ values of 8 and 0.18 mg/kg p.o. for the A and B forms, respectively. Selectivity is retained on repeat dosing. MDL 72,974 did not significantly potentiate the cardiovascular effects of intraduodenually-administered tyramine in anaesthetized rats and had only minor indirect sympathominatic effects in the pithed rat. At MAO-B selective doses the neurotoxic effect of MPTP in mice was blocked.Part of this work was presented at the 7th European Winter Conference on Brain Research (Zreika et al., 1987).     

Striatal 6-[18F]fluorodopa accumulation after combined inhibition of peripheral catechol-O-methyltransferase and monoamine oxidase type B: Differing response in relation to presynaptic dopaminergic dysfunction

The aim was to investigate the effects of inhibition of monoamine oxidase type B (MAO-B) with selegiline alone and the combined inhibition of peripheral catechol-O-methyltransferase (COMT) with entacapone and MAO-B with selegiline on striatal 6-[¹⁸F]fluorodopa (FDOPA) accumulation, and whether the effect of entacapone + selegiline on FDOPA uptake differed depending on the severity of the presynaptic dopaminergic dysfunction. Thus, eight healthy controls, eight de novo patients with Parkinson's disease (PD), and 18 levodopa-treated PD patients were investigated with positron emission tomography (PET). Half of the subjects in each population belonged to the selegiline group and half to the entacapone + selegiline group. Both groups were studied twice with PET using FDOPA. After the first (baseline) FDOPA PET investigation, both groups were on 2 weeks of selegiline treatment, 10 mg daily. Thereafter, the second FDOPA PET was performed for all subjects with a premedication administered 60 min before the PET imaging; one group received 10 mg of selegiline, and the other group received a single 400 mg dose of entacapone coadministered with 10 mg of selegiline. Selegiline treatment alone had no significant influence on striatal FDOPA metabolism. The FDOPA accumulation, expressed as striatal-to-occipital ratios and modified decarboxylation coefficients (k₃R₀), increased significantly after entacapone + selegiline administration in all subject populations. The FDOPA uptake rate constant (K_i) remained virtually unchanged in controls and in de novo patients but decreased significantly in levodopa-treated PD patients after entacapone + selegiline intake. Entacapone + selegiline administration did not influence significantly the unidirectional blood-to-brain clearance for FDOPA (K₁^D) or the relative dopadecarboxylase activity (k₃^D). The changes in the studied parameters after entacapone + selegiline administration probably reflect the effects of entacapone, since entacapone alone has caused similar changes in previous PET studies. Response in FDOPA accumulation to entacapone + selegiline was higher in controls and de novo patients compared with levodopa-treated PD patients. The milder response in levodopa-treated patients might reflect the reduced ability of the degenerated dopaminergic neurons to utilize the prolonged FDOPA availability, produced by entacapone. Synapse 27:336–346, 1997. © 1997 Wiley-Liss, Inc.     

单胺氧化酶B基因微卫星多态与帕金森病的相关分析

目的 研究上海地区汉族人群中单胺氧化酶B(MAOB)基因第二内含子中鸟嘌呤、胸腺嘧啶(GT)二碱基重复的微卫星多态位点与帕金森病(Parkinson’s disease，PD)易患性之间的关系。方法 采用扩增片段长度多态法(Amp—FLP)，在上海汉族人群中选择67例散发PD患者为PD组和204名健康者为对照组，运用微卫星荧光标记—半自动基因分型技术精确计算出微卫星等位基因片段大小，进而分析该多态在PD易患性中的作用。结果 该位点短片段(≤170bp)等位基因的分布在：PD组中明显高于与对照组(x^2=11．28，P=0．001)，而172bp等位基因在PD组中亦明显低于与对照组(x^2=5．16，P=0．023)。结论 MAOB基因GT二碱基重复多态位点与本组PD患者的易患性有关。     

In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-DOPA and dopamine metabolism

Summary Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nervertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism underbasal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the cheese effect such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.     

Histochemical localisation of monoamine oxidase A and B in rat brain

Summary The histochemical distribution of monoamine oxidase A and B in rat brain was investigated using a coupled peroxidatic technique with benzylamine and tyramine as substrates and clorgyline and (–)-deprenyl as selective inhibitors. Benzylamine oxidase was absent in all areas. Both forms of monoamine oxidase were present, at low levels, in all areas; in addition several regions showed high activity of one or other form or both. Substantial activity of monoamine oxidase B was identified in the pineal gland, the lining of the ventricles, several hypothalamic regions, and the raphe nuclei. The locus coeruleus and interpeduncular nucleus possessed considerable type A activity. The substantia nigra and striatum showed no staining above the low general level, although the ventral tegmental area showed higher levels of both A and B.In general, noradrenaline-containing neuronal cell body areas showed monoamine oxidase A, and 5-hydroxytryptamine-rich areas monoamine oxidase B. There was no consistent enrichment of either in corresponding dopamine-rich regions. Monoamine oxidase thus appears to have a different role in these three types of neuron.The low level of monoamine oxidase B in the nigrostriatal tract may help to explain the resistance of the rat to MPTP toxicity.     

Comparative effects of repeated administration of dopamine agonists on circling behavior in rats

Summary. A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation. Received February 8, 2000; accepted March 8, 2000     

单胺氧化酶B基因多态与早发帕金森病的相关性

目的 探讨单胺氧化酶B(MAO-B)基因型和等位基因与早发帕金森病(early-onset Parkinson's disease,EOPD)的关系.方法 采取聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,研究65例EOPD患者(<50岁)、60例晚发PD(late-onset Parkinson's disease,LOPD)患者(≥60岁)和66名健康对照者(<50岁)的基因型频率和等位基因频率的分布差异.结果 EOPD组的AA基因型频率(49/65,75.4%)高于健康对照组(34/66,51.5%),差异有统计学意义(x2=8.075,P=0.018);LOPD组分别与EOPD组、健康对照组的从基因型频率比较,差异无统计学意义;男性EOPD组分别与男性健康对照组、男性LOPD组,女性EOPD组分别与女性健康对照组、女性LOPD组的AA基因型频率比较,差异无统计学意义;男性LOPD组与男性健康对照组、女性LOPD组与女性健康对照组的AA基因型频率比较,差异无统计学意义.EOPD组的A等位基因频率(107/130,82.3%)高于健康对照组(87/132,65.9%),差异有统计学意义(X2=9.165,P=0.002);LOPD组分别与EOPD组、健康对照组的A等位基因频率比较,差异无统计学意义;男性EOPD组的A等位基因频率(60/70,85.7%)高于男性健康对照组(51/72,70.8%),差异有统计学意义(x2=4.606,P=0.032);女性EOPD组的A等位基因频率(47/60,78.3%)高于女性健康对照组(36/60,60.0%),差异有统计学意义(x2=4.728,P=0.030);男性LOPD组分别与男性EOPD组、男性健康对照组,女性LOPD组分别与女性EOPD组、女性健康对照组的A等位基因频率比较,差异均无统计学意义.结论 MAO-B的从基因型频率增高是EOPD组发病的危险因素;MAO-B的A等位基因频率增高是EOPD组、男性EOPD组及女性EOPD组发病的危险因素.     

中国人群单胺氧化酶-B基因多态性与帕金森病相关性研究

目的 探讨人多巴胺代谢酶—单胺氧化酶B(MAO—B)基因内含子13内核苷酸A／G多态性与帕金森病(Parkinson’s disease，PD)遗传易患性的关系。方法 利用聚合酶链反应—变性高压液相技术(PCR—DHPLC)分析了MAO—B基因13内含子A／G多态性在PD患者与健康对照之问分布频率的差异。结果 野生基因型(A或AA)在总体PD或对照组中的分布频率77．8％和74．0％，杂合基因型A／G的频率分别为11．7％和8．4％；突变基因型(G／G或G)分别为10．5％和17．5％，使患PD的危险度降低1．8倍(P=0．04)；按发病年龄分组，突变基因型使患者早发PD的危险度降低2．4倍(P=0．031)。无论从总体分析，还是按发病年龄或性别分组，等位基因在各个组的分布频率差异无显著意义。结论 MAO—B的A／A(A)基因型是PD发生的危险因素，与PD的遗传易患性有关，对早发PD影响较大。     

Effect of monoamine oxidase inhibition on the regional cerebral blood flow response to circulating noradrenaline

The effect of an acute i.v. infusion of noradrenaline (NA) on regional cerebral blood flow (rCBF) was investigated in the awake rat using [¹⁴C]iodoantipyrine as diffusible tracer. The contribution of vascular monoamine oxidase (MAO) to the efficiency of the enzymatic blood-brain barrier (BBB) to catecholamines was assessed by measuring the multiregional cerebrovascular response to circulating NA given alone or after i.v. administration of the monoamine oxidase inhibitor, clorgyline. Since i.v. infusion of NA elevates blood pressure, the influence of NA on the cerebrovascular bed was first studied by determining the relationship between rCBF and the mean arterial pressure (MAP). When the MAP was only slightly increased (to approximately 130 mm Hg), a trend to flow decrease under NA infusion was observed. Secondly, we compared the effects of NA or rCBF in animals treated or not treated with clorgyline. This was performed under moderate hypertension (within the ‘autoregulated’ range of MAP) to avoid any risk of mechanical damage to the BBB. Clorgyline administration alone did not significantly modify rCBF, but the subsequent i.v. infusion of NA induced an increase in rCBF (weighted mean 14%) in all structures investigated. The differences being statistically significant (P < 0.05) in 5 out of 13 structures by up to 20%. Compared to studies involving disruption of the morphological BBB in which plasma NA elicits a widespread important increase in blood flow, the weak cerebrovascular effects we observed provide indirect evidence for the efficiency of the BBB to catecholamines in the conscious rat within the autoregulated range of arterial pressure. Conversely, the NA-induced vasodilation obtained after inhibition of vascular MAO shows that the enzymatic BBB participates in the overall restriction of the permeability to NA, with a fairly homogeneous regional distribution.     

Peripheral blood cell activities of monoamine oxidase B and superoxide dismutase in Parkinson's disease

Summary Monoamine oxidase type B (MAO-B) and superoxide dismutase (SOD) are two enzyme stystems that are potentially relevant to an oxidative stress model of Parkinson's disease (PD) causation. Activities of MAO-B in platelets (nmol/10⁸ cells/hr) and total SOD in lymphocytes (U/mg protein) were assayed among 28 cases of idiopathic PD and 22 controls. As anticipated, MAO-B was lowest in PD cases on selegiline (L-deprenyl) therapy (mean 1.10). There was a slight deficit of MAO-B among male cases not taking selegiline compared to controls (3.78 vs. 4.15), but the opposite trend was observed for females (6.18 vs. 4.16). SOD was slightly higher in cases (7.40), than controls (6.81). Excess SOD among PD cases was seen irrespective of gender, age, or selegiline treatment, although none of the differences was statistically significant Future research on SOD should take advantage of the availability of assays specific for the cytosolic and mitochondrial forms of the enzyme.     

Selective reduction of monoamine oxidase A and B in the frontal cortex of subordinate rats

We have previously shown that subordination causes a reduction in the levels of 5-hydroxytryptamine and dopamine selectively in the frontal cortex [6]. These monoamines are catabolised mainly by the enzyme monoamine oxidase (MAO) which exists in two isoforms. MAO-A and MAO-B. The present study was carried out to determine whether there is any change in the activity of these two iso-enzymes induced by subordination and if any such alteration is confined to the frontal cortex. The animal model of dominance-subordination used was a worker-parasite paradigm in male Wistar rats. The enzyme activities were measured in five brain regions, the frontal cortex, entorhinal cortex, hippocampus, hypothalamus and striatum, using kynuramine as the substrate. Clorgyline and -deprenyl were used in vitro to block the activities of MAO-A and MAO-B, respectively. There was a significant (P < 0.001) reduction in the activity of MAO-A as well as MAO-B selectively in the frontal cortex of the subordinate animals. This finding may suggest a reduced neurotransmitter turnover in the serotonergic and dopaminergic neurons terminating in the frontal cortex.     

Effect of aging on lazabemide binding,monoamine oxidase activity and monoamine metabolites in human frontal cortex

Summary Age-related modifications of monoamine oxidase-A and -B (MAO-A and MAO-B) and amine metabolite concentrations were studied in human frontal cortex taken postmortem from 22 subjects of various ages (21–75 years). Qualitative and quantitative analysis for MAO-B was provided by kinetic studies with a specific radioligand, [³H]lazabemide. The data demonstrated a significant (P < 0.05) positive correlation between the density of [³H]lazabemide binding sites (B_max) and age of the subject, without showing an apparent modification in the dissociation constant (K_D) of the radioligand. In parallel experiments, MAO-B but not MAO-A activity was shown to correlate with age (P < 0.05). The concentrations of the amine metabolites 4-hydroxy-3-methoxyphenylacetic acid (HVA), 5-hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) were all devoid of a correlation with age. Neither did the concentrations of these metabolites relate to the respective subject's MAO-B enzymatic activity nor to [³H]lazabemide B_max. A correlation, though rather weak, was obtained between MAO-A activity and MHPG concentration (P=0.045). The MAO-A and -B enzyme characteristics in subjects who had committed suicide (n=9) did not differ from those of subjects deceased for other causes (n=13). Among the measured monoamine metabolites the concentrations of DOPAC and HVA were higher in the suicide versus control group (P < 0.05). The present data confirm in a direct manner that the increase in MAO-B activity in aging brain is due to an enhancement of the number of active sites of the enzyme and not through modifications of its kinetic characteristics. Furthermore, that neither the characteristics nor the activity of the enzyme are changed in the frontal cortex of suicide victims compared to control subjects.     

Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle and late phase of Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder with unclear aetiology. Cognitive impairment in AD might be associated with altered serotonergic system. The aim of the study was to determine platelet serotonin (5-HT) concentrations and platelet monoamine oxidase type B (MAO-B) activity in patients with different severity of AD. Platelet 5-HT concentrations and MAO-B activity were determined spectrofluorimetrically in 74 female patients with AD (NINCDS-ADRDA, DSM-IV-TR criteria), subdivided according to the Mini Mental State Examination (MMSE) scores in three groups with a) 23 patients in early (MMSE scores 19–24), b) 23 patients in middle (MMSE 10–18), and c) 28 patients in late (MMSE 0–9) phase of AD, and in 49 age-matched healthy women. Platelet 5-HT concentrations and MAO-B activity were similar between all patients with AD and healthy subjects, but were significantly lower in patients in the late phase of AD than in other phases of AD, and in healthy controls. The significant correlations were found between MMSE scores and platelet 5-HT concentrations, MAO-B activity and age. Lower platelet 5-HT concentration and MAO-B activity in the late phase of AD suggested that these markers might indicate severity and/or clinical progress of AD.     

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition

Summary The cheese effect, potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible nonselective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with nonselective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.     

Effect of monoamine oxidase inhibition on catecholamine levels: evidence for synthesis but not storage of epinephrine in rat spinal cord

Epinephrine levels in the intermediolateral cell group in the rat spinal cord are very low, although there is a dense projection to this region from cells containing all the enzymes required for epinephrine biosynthesis. One explanation for this finding is that epinephrine in the nerve terminals is degraded as soon as it is synthesized, so that no epinephrine is actually stored in synaptic vesicles. To test this hypothesis, epinephrine levels were measured in spinal cord of rats pretreated with an inhibitor of monoamine oxidase, the major enzyme involved in epinephrine degradation. Selected other tissues (i.e. brainstem, hypothalamus, adrenal gland, superior cervical ganglion) were examined for comparison. Pargyline treatment (75 mg/kg i.p., 4 h prior to sacrifice) increased catecholamine levels in spinal cord, hypothalamus, and brainstem. However, the percent increase in epinephrine in the spinal cord and brainstem was much larger than that for dopamine and norepinephrine in the 3 central nervous system regions studied, as well as larger than that for epinephrine in the hypothalamus. These results suggest that phenylethanolamine N-methyltransferase (PNMT)-containing terminals in the rat spinal cord can synthesize epinephrine, but that little if any epinephrine is stored in synaptic vesicles due to the rapid metabolism of cytoplasmic catecholamines by monoamine oxidase. In contrast, pargyline pretreatment had no effect on catechol levels in the adrenal gland, suggesting that little metabolism of catecholamines takes place in those epinephrine-synthesizing cells. Furthermore, since pargyline pretreatment increased norepinephrine levels but decreased dopamine levels in the superior cervical ganglion, it is suggested that most of the dopamine in that sympathetic ganglion is present as a precursor to norepinephrine in noradrenergic postganglionic sympathetic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

单胺氧化酶B基因13内含子G/A多态性与帕金森病的关系

目的探讨多巴胺代谢酶———单胺氧化酶B(MAO-B)基因13内含子G/A多态性与帕金森病(PD)的关系。方法应用PCR-限制性片段长度多态性(RFLP)技术检测166例PD患者(其中早发型52例,晚发型114例)和170名正常对照者的MAO-B基因13内含子G/A位点的基因型和等位基因,比较分析其分布情况。结果 PD组与正常对照组MAO-B基因野生型(AA)、杂合型(AG)、突变型(GG)频率及等位基因频率差异无统计学意义;PD早发型亚组的AA型(80.8%)和A等位基因型频率(86.5%)显著高于晚发型亚组(60.5%,71.5%)及正常对照组(60.6%,71.5%)(均P<0.05);PD晚发型亚组与正常对照组各基因型和等位基因频率的差异无统计学意义;PD男性及女性亚组与同性别正常对照组的基因型和等位基因频率的差异均无统计学意义。结论 MAO-B基因13内含子AA型和A等位基因频率增高是PD发病的危险因素之一;MAO-B基因13内含子G/A多态性与PD,尤其是与早发型PD的遗传易感性有关。     

Effects of monoamine oxidase inhibition by selegiline on concentrations of noradrenaline and monoamine metabolites in CSF of patients with Alzheimer's disease

Summary A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical, effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.     

海马注射β-淀粉样蛋白-40对AD大鼠脑组织MAO、脂褐素表达的影响及通络救脑口服液对其的干预作用

目的探讨大鼠大脑海马注射β-淀粉样蛋白1--40对MA0、脂褐素表达的影响及通络救脑口服液对其的干预作用。方法140只Sprague--Dawley（SD）大鼠随机分为空白对照组、假手术组、阴性对照组、阳性对照组、实验组（48，24，12mg·kg^-1·d^-1）共7组。采用大脑海马立体定向注射凝聚态β-淀粉样蛋白14。诱导老年性痴呆（Alzheimer’Sdisease，AD）动物模型。药物干预4周，第5周应用分光光度法检测大鼠大脑组织MA0酶活性的变化，采用荧光分光光度法检测脂褐素的含量变化，以及通络救脑口服液对上述指标的影响。结果模型组大鼠脑组织MA0、脂褐素含量分别为（7．88±0．76）和（5．42士0．24），MAO、脂褐素含量显著多于假手术组MA0含量为（5．38±0．52），脂褐素含量为（4．16±0．18），P〈0．05），表明模型组MA0、脂褐素表达水平升高；与模型组比较，盐酸多奈哌齐组MA0含量为（7．08±0．39），脂褐素含量为（4．91±0．23）、通络救脑口服液低、中、高各剂量组MAO分别为（7．07±0．81，7．13士0．53，6．36±0．36）；脂褐素分别为（4．89±0．17，4．52士0．20，4．23±0．35），MAO与脂褐素含量显著减少。结论大脑海马注射β-淀粉样蛋白1-40后大鼠脑组织MAO、脂褐素表达水平明显增高，而通络救脑口服液可以降低海马组织MA0、脂褐素的含量，通过其抗氧化而发挥其抗老年性痴呆的作用。     

Effect of microiontophoretic application of dopamine on subthalamic nucleus neuronal activity in normal rats and in rats with unilateral lesion of the nigrostriatal pathway

The subthalamic nucleus (STN) receives dopamine inputs from the substantia nigra but their implication in the pathophysiology of parkinsonism is still debated. Extracellular microrecordings were used to study the effect of microiontophoretic injection of dopamine and the D1 receptor agonist SKF 38393 on the activity of STN neurons in normal and 6-hydroxydopamine-lesioned rats under urethane anaesthesia. Dopamine and SKF induced an increase in the firing rate of the majority of STN neurons in both normal and 6-OHDA rats. In rats with 6-OHDA lesions, the percentage of firing rate increase did not differ from that of controls. When GABA, glutamate and dopamine were all applied to the same individual STN neurons, GABA induced an inhibitory effect and glutamate and dopamine caused an excitatory effect in both groups. This excitatory response was suppressed by the application of GABA. Systemic administration of apomorphine provoked a decrease in the firing rate of STN neurons in rats with 6-OHDA lesions. These results show that dopamine exerts an excitatory influence on STN neurons, suggesting that the inhibitory effect induced by the systemic injection of apomorphine is due to the GABAergic inputs from the globus pallidus as predicted by the current model of basal ganglia organization. In addition, we show that dopamine, GABA and glutamate can act on the same STN neuron and that GABA can reverse the excitatory effect of dopamine and glutamate, suggesting the predominant influence of GABAergic inputs to the subthalamic nucleus.