帕金森病药物治疗的遗传药理学研究进展

帕金森病是中老龄人中常见的神经退行性疾病,主要以拟多巴胺类药物治疗为主,但药物反应个体差异较大。与多巴胺代谢相关基因的遗传变异是导致药物反应个体差异的重要原因之一。目前国内研究主要集中在遗传多态性与帕金森病易感性之间的关系方面,而对帕金森病治疗的遗传药理学研究相对较少。该文对多巴胺转运体、多巴胺代谢酶和作用的受体等相关基因的遗传多态性与帕金森病治疗反应个体差异相关性方面的研究进行了一个较为全面的阐述。     

Istradefylline,a novel adenosine A2A receptor antagonist,for the treatment of Parkinson’s disease

Dopamine replacement therapy effectively treats the early motor symptoms of Parkinson’s disease (PD). However, its association with the development of motor complications limits its usefulness in late stages of the disease. Adenosine A_2A receptors are localised to the indirect striatal output function and control motor behaviour. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD. Istradefylline is a novel adenosine A_2A receptor antagonist currently in Phase III clinical trials for efficacy in patients with PD; results from Phase II clinical trials demonstrated that it provides a clinically meaningful reduction in ‘off’ time and an increased ‘on’ time with non-troublesome dyskinesia in levodopa-treated patients with established motor complications, and is safe and well tolerated.     

The effects of environmental neurotoxicants on the dopaminergic system: A possible role in drug addiction

Humans are routinely exposed to a vast array of environmental neurotoxicants, including pesticides, endocrine disrupters, and heavy metals. The long-term consequences of exposure have become a major human health concern as research has indicated strong associations between neurotoxicants and a variety of dopamine-related neurological disorders. Developmental exposure to pesticides including paraquat, organochlorines, and rotenone produce alterations in the dopaminergic system and has been linked to neurodegenerative disorders, including Parkinson's disease. Endocrine disrupters such as Bisphenol A, mimic estrogenic activity and impact various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse. A second class of endocrine disrupters, the polychlorinated biphenyls, may act directly on dopaminergic processes to disrupt the dopamine system and produce Parkinson-like symptoms. Exposure to the heavy metal lead enhances dopaminergic activity and has been associated with attention deficits, Alzheimer's disease, and increased drug sensitivity. Manganese exposure, in contrast, results in dopamine deficiencies and Parkinson-like symptoms. Therefore, this commentary will discuss the effects and consequences that exposure to these three classes of environmental neurotoxicants have on the dopamine system and related behaviors and disorders. Finally, the recent hypothesis that exposure to environmental compounds which have effects on dopaminergic neurotransmission, including 2,4-dichlorophenoxyacetic acid, Bisphenol A, and multiple heavy metals, may potentiate drug-induced behaviors and increase the brain's vulnerability to drug addiction will be discussed.     

腺苷A_1受体阻断剂对大鼠海马BDNF蛋白表达及内质网的影响

目的探讨腺苷A1受体阻断对大鼠海马BDNF蛋白表达及内质网功能的影响。方法采用免疫组化技术观察腺苷A1受体特异性阻断剂8-环戊-1,3-二丙基黄嘌呤(DPCPX)对大鼠海马颗粒细胞BDNF蛋白表达的影响;采用透射电镜技术观察DPCPX对大鼠海马神经元内质网数量的影响。结果DPCPX(0.1 mg.kg-1,ip,15 d)可增加海马颗粒细胞BDNF蛋白表达阳性细胞的数目。DPCPX(0.5 mg.kg-1,ip,15 d)能增加BDNF蛋白在海马颗粒细胞的表达,使阳性细胞数目明显增加、染色加深;同时增加大鼠海马神经元中内质网的数量,使内质网密度增加。结论DPCPX可促进大鼠海马颗粒细胞内BDNF蛋白表达和诱导海马神经元内质网功能增强。     

Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.     

Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs

Introduction: Long acting muscarinic receptor antagonists (LAMA) reverse airflow obstruction by antagonizing para-sympathetic bronchoconstricting effects within the airways. For years, tiotropium, has been the cornerstone LAMA for chronic obstructive pulmonary disease (COPD) management. Recently, new agents, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide, have been developed and introduced into clinical practice.

Areas covered: This article reviews the clinical efficacy and adverse effects of currently available LAMAs in COPD treatment as well as developing LAMAs in early clinical trials and preclinical studies (V0162, TD-4208, CHF 5407, AZD9164, AZD8683, bencycloquidium). In addition, a new class of molecule that combines muscarinic antagonist and β2-adrenergic properties (MABA) is described and current developmental progress discussed (GSK-961081, THRX-200495).

Expert opinion: Future key areas for developing drugs for the management of COPD include prolonged duration of action, optimal delivery systems, synergistic combinations with other drugs, maximization of benefits and minimization of adverse effects. The development of new LAMA and MABA molecules provides exciting progress towards simpler and more effective COPD management.     

Advances in the treatment of diabetic renal disease: focus on losartan

SUMMARY

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), and given that treating this condition is a considerable economic burden, the prevention of ESRD is a major public health goal. The renin-angiotensin system (RAS) is aberrantly activated in patients with diabetes. Angiotensin II (AII), a downstream effector of the RAS, has haemodynamic and non-haemodynamic effects that contribute to the development and progression of nephropathy. For patients with type 2 diabetes mellitus (T2DM) and hypertension, an AII receptor blocker (AIIRB) is recommended as the first drug that should be used. This review will focus on the rationale for the use of losartan as a treatment for nephropathy associated with T2DM. In animal models of diabetes, losartan reduced proteinuria and conferred renal protection. In RENAAL (Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), the first major randomised

trial that investigated the benefit of losartan in patients with T2DM and nephropathy, losartan significantly reduced the risk of a doubling of serum creatinine and progression to ESRD, significantly lowered the levels of proteinuria and slowed the rate of decline in glomerular filtration rate. This review also discusses other clinical trials of losartan and other AIIRBs in T2DM, and considers alternative mechanisms by which losartan may be exerting its effects. The collective experience in treatment trials highlighted in this review indicate that losartan and other AIIRBs can reduce blood pressure and the progression of proteinuria in diabetic renal disease. However, losartan is thus far the only AIIRB that has been shown to reduce significantly the risk of ESRD and cardiovascular events in patients with T2DM. Its use in hypertensive patients with T2DM and nephropathy may play an important role in reducing the burden of ERSD.     

Structure-Activity Relationship Studies of CNS Agents,Part 31[1]: Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment — New 5-HT1A Receptor Ligands

Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines ( 3, 4a, 4b, 6–9 , and 12–13 ) and 2-(n-propyl)-1,2,3,4-tetrahydroisoquinolines ( 5a, 5b, 11a , and 11b ) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT_1A/5-HT_2A and α₁ receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT_1A/5-HT_2A/α₁ receptor ligands. Compounds 3, 4a, 4b, 7–9a with the highest affinity for 5-HT_1A receptors (K_i = 4–54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8 , and 9a behaved like weak antagonists of postsynaptic 5-HT_1A receptors, 4b and 7 may be classified as potential partial 5-HT_1A receptor agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT_1A receptor agonist.     

Neuroprotective effects of a selective N-methyl-D-aspartate NR2B receptor antagonist in the 6-hydroxydopamine rat model of Parkinson's disease

1. Current pharmacotherapies for the treatment of Parkinson's disease (PD) are largely symptomatic and do not attenuate the characteristic nigral (dopamine) cell loss. 2. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we investigated the novel, potentially neuroprotective compound BZAD-01, which is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist selective for the NR2B subunit. 3. Forty female Sprague-Dawley rats were pretreated with either 10 mg/kg BZAD-01 or vehicle (5% sucrose and 0.1% ascorbate) in their drinking water for 11 days prior to and for 3 days following 6-OHDA surgery. During surgery, rats received an injection of either a toxic dose of 16 microg 6-OHDA or a non-toxic dose of 1 microg 6-OHDA (sham) into the medial forebrain bundle. A series of behavioural tests, including curling (measuring body axis bias), head position bias and narrow beam, was performed fortnightly for 8 weeks after surgery to assess the effects of BZAD-01 pretreatment on parkinsonism. Drug-induced rotational asymmetry was also assessed just before rats were killed. Post-mortem immunohistochemistry was performed to quantify the degree of nigral dopamine cell loss. 4. Pretreatment of 6-OHDA-lesioned rats with BZAD-01 significantly reduced the amount of dopamine cell loss and significantly improved all behavioural measures. Furthermore, there was no significant difference in any of the behavioural measures between lesioned rats pretreated with BZAD-01 and rats that underwent sham surgery.     

Good night and good luck: Norepinephrine in sleep pharmacology

Sleep is a crucial biological process that is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- and sleep-promoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE transmission and the wake-promoting pathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic receptor antagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake- and sleep-promoting drugs within the framework of the brain arousal systems.