Therapeutic use of melatonin in schizophrenia-more than meets the eye!

Adjunctive melatonin use in schizophrenia, as supported by a modicum of evidence, has multiple transcending chronobiotic actions, including fixing concurrent sleep problems to bona fide augmentative antipsychotic actions, mitigating the risk of tardive dyskinesias, curbing the drastic metabolic syndrome and ultimately providing neuroprotective actions. Its use is rather an art than science!     

联合使用神经保护剂治疗急性脑梗死的临床研究

目的　研究脑梗死后早期应用神经保护剂对患者神经功能恢复的影响。　方法　 12 0例急性脑梗死患者随机分为治疗组A(抗凝 Ca 拮抗剂 )、治疗组B(抗凝 自由基清除剂 )、治疗组C(抗凝 Ca 拮抗剂 自由基清除剂 )、对照组 (仅使用抗凝治疗 )。在治疗前及治疗后 1个月分别从神经功能缺损及残疾 /生活能力水平两方面进行评价。　结果　B、C两组的疗效在神经功能缺损评分和Barthel指数分别为 7 61± 5 2 6、7 2 6± 5 0 6和 82 3 7± 3 0 61、84 49± 3 1 5 3皆明显优于对照组的 9 2 1± 5 42和 70 0 2± 3 0 2 4(P <0 0 5 ) ,A组与对照组、B组与C组疗效差异无显著性 (P >0 0 5 )。　结论　联合使用适当的神经保护剂能提高脑梗死的疗效     

抗ICAM-1抗体联合IGF-1治疗猫脑缺血再灌注损伤的有效性研究

目的 评价联合应用抗ICAM-1抗体和IGF-1在治疗脑缺血再灌注损伤中的作用.方法 24只健康家猫,随机分成4组:对照组、抗ICAM-1抗体治疗组、IGF-1治疗组和联合治疗组,每组6只动物,采用经眼眶入路夹闭大脑中动脉M2段的方法建立家脑猫缺血再灌注模型.于再灌注后3d和7d进行Philips神经功能缺损评分、磁共振T2WI高信号体积测量和TUNAL法凋亡细胞计数.结果 联合治疗组7d时神经功能评分增加、最终梗死体积缩小、凋亡细胞数减少(分别为:40.83±4.36;0.49±0.06;21.59±7.28),明显优于抗ICAM-1抗体治疗组(分别为:55.83±3;1.03±0.08;34.03±0.08)和IGF-1治疗组(分别为:61.00±2.96;0.73±0.07;39.73±0.07),P＜0.05.结论 应用抗ICAM-1抗体和IGF-1治疗脑梗死,能够从多环节减轻和阻断脑缺血再灌注损伤的病理过程,显著提高脑梗死的疗效.     

Luteolin from Purple Perilla mitigates ROS insult particularly in primary neurons

Increased attention has been paid to the role of oxidant/antioxidant imbalance in neurodegenerative process and pharmaceutical neuroprotective interventions. Food-derived compound luteolin possesses multitarget actions including reactive oxygen species (ROS)-scavenging activity in cultured human endothelial cells or permanent immature rat oligodendrocytes. This study aims to elucidate whether luteolin has a neuroprotective tendency toward ROS-insulted neural cells. The present results showed that luteolin, isolated from the ripe seed of Perilla frutescens (L.) Britt., markedly reversed hydrogen peroxide-induced cytotoxicity in primary culture cortical neurons but not in cultured human neuroblastoma cells. Upon the ROS-insulted primary neurons, luteolin concentration-dependently enhanced neuronal cell survival with efficacy higher than and potency similar to vitamin E. Additionally, luteolin significantly attenuated the increase in ROS production and prevented the decreases in activities of mitochondria, catalase, and glutathione in ROS-insulted primary neurons. Thus, luteolin functions by neuroprotection possibly through a rebalancing of pro-oxidant-antioxidant status. This agent points to possible interventions for preventing neurodegenerative diseases such as cerebral ischemia, Parkinson's disease, and Alzheimer's disease, as well as for improving brain aging.     

超早期溶栓联合神经保护剂治疗急性脑梗死的临床研究

目的：研究尿激酶（ＵＫ）溶栓溶栓治疗的疗效、最佳时机、安全性及神经保护剂对溶栓疗效的影响。方法：４５例急性脑梗死患者,起病６小时内３０例,６～１２小时１５例,根据起病时间及是否使用神经保护剂分为Ａ、Ｂ、Ｃ三组,快速静脉商注尿激酶５０～８０万单位,另设对照组３０例,分别对治疗前,后患者神经功能缺损及疗效进行定。结果： 与对照组相比神经功能缺损评分下降显著,Ａ、Ｂ组（〈６小时组）Ｐ〈０．０１,Ｃ组）６     

Safety,tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects*

ABSTRACT

Objective: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cuss) exposure range of 50-300 μmol/L in healthy young and elderly subjects.

Research design and methods: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8‐h and 72‐h intravenous infusions of NXY‐059 in healthy young (20–45 years) and elderly (55–75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8‐h and 72‐h intravenous infusions of NXY‐059 in these subjects, using blood and urine samples taken during and after NXY‐059 infusion as well as the doses administered.

Results: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY‐059 and placebo subjects were similar, although headache was more common in the NXY‐059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8‐h and 72‐h infusions was observed, and clearance did not change with dose.

Conclusions: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8‐h and 72‐h infusions of NXY‐059 at doses resulting in an average Cu_ss in the 52–317?µmol/L range.     

The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI

Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occurs. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determine patient outcome. For mild and moderate TBI, the pathomechanism is similar but much less frequent and ischemic cell death is unusual, except with mass lesions. Involvement of mitochondria in acute post-traumatic neurodegeneration has been extensively studied during the last decade, and there are a number of investigations implicating the activation of the mitochondrial permeability transition pore (mPTP) as a “critical switch” which determines cell survival after TBI. Opening of the mPTP is modulated by several factors occurring after a severe brain injury. Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of mPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.     

Neuroprotective effect of epidermal growth factor plus growth hormone-releasing peptide-6 resembles hypothermia in experimental stroke

Abstract

Background: Combined therapy with epidermal growth factor (EGF) and growth hormone-releasing peptide 6 (GHRP-6) in stroke models has accumulated evidence of neuroprotective effects from several studies, but needs further support before clinical translation. Comparing EGF + GHRP-6 to hypothermia, a gold neuroprotection standard, may contribute to this purpose.

Objectives: The aims of this study were to compare the neuroprotective effects of a combined therapy based on EGF + GHRP-6 with hypothermia in animal models of (a) global ischemia representing myocardial infarction and (b) focal brain ischemia representing ischemic stroke.

Methods: (a) Global ischemia was induced in Mongolian gerbils by a 15-min occlusion of both carotid arteries, followed by reperfusion. (b) Focal brain ischemia was achieved by intracerebral injection of endothelin 1 in Wistar rats. In each experiment, three ischemic treatment groups – vehicle, EGF + GHRP-6, and hypothermia – were compared to each other and to a sham-operated control group. End points were survival, neurological scores, and infarct volume.

Results: (a) In global ischemia, neurological score at 48–72 h, infarct volume, and neuronal density of hippocampal CA1 zone in gerbils treated with EGF + GHRP-6 were similar to the hypothermia-treated group. (b) In focal ischemia, the neurologic score and infarct volume of rats receiving EGF + GHRP-6 were also similar to animals in the hypothermia group.

Discussion: With hypothermia being a good standard neuroprotectant reference, these results provide additional proof of principle for EGF and GHRP-6 co-administration as a potentially neuroprotective stroke therapy.     

A novel Na+/Ca2+ channel blocker, NS-7, suppresses hypoxic injury in rat cerebrocortical slices

The substance 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) has been developed recently as a cerebroprotective compound with Na⁺ and Ca²⁺ channel blocking action. In the present study, the effect of NS-7 in an in vitro model of hypoxic injury was examined and the possible involvement of Na⁺ and Ca²⁺ channels in the hypoxic injury subsequently determined. When slices of rat cerebral cortex were exposed to hypoxia/glucose deprivation followed by reoxygenation and restoration of the glucose supply, marked leakage of lactate dehydrogenase (LDH) occurred 3–6 h after reoxygenation. This hypoxia/reoxygenation-induced injury was blocked almost completely by the removal of extracellular Ca²⁺ or by chelating intracellular Ca²⁺ with 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca²⁺ channel blocker ω-conotoxin GVIA and the P/Q-type Ca²⁺ channel blocker ω-agatoxin IVA significantly reduced LDH leakage, although neither of these Ca²⁺ channel blockers alone, nor nimodipine, an L-type Ca²⁺ channel blocker, was effective. On the other hand, several Na⁺ channel blockers, including tetrodotoxin, local anaesthetics and antiepileptics, significantly reduced the hypoxic injury. NS-7 (3–30 μM) concentration-dependently inhibited LDH leakage caused by hypoxia/reoxygenation, but had no influence on the reduction of tissue ATP content and energy charge during hypoxia and glucose deprivation. It is suggested that blockade of Na⁺ and Ca²⁺ channels is implicated in the cerebroprotective action of NS-7. Received: 10 March 1998 / Accepted: 19 April 1998