l-3-n-Butylphthalide attenuates β-amyloid-induced toxicity in neuroblastoma SH-SY5Y cells through regulating mitochondrion-mediated apoptosis and MAPK signaling

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid-β protein (Aβ), the hallmark of AD, invokes a cascade of mitochondrial dysfunction and eventually leads to neuronal death. l-3-n-Butylphthalide (l-NBP) has shown the potent neuroprotective effects in stroke and AD animal models. The present study is to evaluate the neuroprotective effect of l-NBP on Aβ_25–35-induced neuronal injury and the possible mechanism in the human neuroblastoma SH-SY5Y cells. Our results showed that l-NBP significantly attenuated Aβ_25–35-induced cell death and reduced neuronal apoptosis. l-NBP significantly inhibited Aβ_25–35-induced mitochondrial dysfunction, including mitochondrial membrane potential reduction, and reactive oxygen species production. Furthermore, l-NBP could partially reverse the elevations of Aβ_25–35-induced active caspase-3, caspase-9, and cytochrome c expressions, and the downregulation of anti-apoptosis protein Bcl-2. Moreover, l-NBP markedly inhibited the activations of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway. These results demonstrated that l-NBP was capable of protecting neuronal cells from Aβ_25–35-induced toxicity through a mitochondrial-dependent apoptotic pathway. Thus, l-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of AD.     

Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with <Emphasis Type="SmallCaps">l</Emphasis>-NAME-induced hypertension

Inhibition of nitric oxide synthesis with N ^ω -nitro-l-arginine methyl ester (l-NAME) induces marked hypertension and oxidative stress. Curcumin (CUR) has been shown strong antioxidant property. Tetrahydrocurcumin (THU), a major metabolite of CUR, possesses several pharmacological effects similar to CUR; however, it is less studied than CUR. We investigated whether CUR and THU could prevent vascular dysfunction and inhibit development of hypertension in l-NAME-treated rats. Male Sprague–Dawley rats were administered with l-NAME (50 mg/kg/day) in drinking water for 3 weeks. CUR or THU (50 and 100 mg/kg/day) was fed to animals simultaneously with l-NAME. l-NAME administration induced increased arterial blood pressure and elevated peripheral vascular resistance accompanied with impaired vascular responses to angiotensin II and acetylcholine. CUR and THU significantly suppressed the blood pressure elevation, decreased vascular resistance, and restored vascular responsiveness. The improvement of vascular dysfunction was associated with reinstating the marked suppression of eNOS protein expression in the aortic tissue and plasma nitrate/nitrite. Moreover, CUR and THU reduced vascular superoxide production, decreased oxidative stress, and increased the previously depressed blood glutathione (GSH) and the redox ratios of GSH in l-NAME hypertensive rats. The antihypertensive and some antioxidant effects of THU are apparently more potent than those of CUR. This study suggests that CUR and THU prevented the development of vascular dysfunction induced by l-NAME and that the effects are associated with alleviation of oxidative stress.     

Involvement of NO/cGMP pathway in toluene-induced locomotor hyperactivity in female rats

Rationale Nitric oxide (NO) is implicated in the acute locomotor activating effects of some addictive drugs such as amphetamine, caffeine, and PCP, but has not been investigated in the case of toluene.Objectives This study determined the contribution of the NO-cyclic GMP (cGMP) pathway to locomotor stimulant effects of toluene.Methods Locomotor activity was measured for 90 min immediately following toluene (500–1,000 mg/kg, IP) or corn oil treatments in Sprague-Dawley female rats. A NO generator, sodium nitroprusside (SNP) (3 and 6 mg/kg), a NO precursor, l-arginine (l-Arg) (250 mg/kg), a NO synthase inhibitor,N^G-nitro-l-arginine methyl ester (l-NAME) (5–20 mg/kg, IP), and a soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 mg/kg) were injected 5 min before toluene (750 mg/kg, IP) treatment. The combination effects of SNP with l-NAME, l-arginine with l-NAME, SNP with ODQ and l-arginine with ODQ on toluene-induced locomotor hyperactivity were also determined.Results The locomotor hyperactivity induced by toluene was significantly inhibited by SNP and l-arginine, but enhanced by l-NAME and ODQ. SNP and l-arginine completely reversed the combined effects of l-NAME and toluene to a basal level and abolished the enhancing effects of ODQ.Conclusions The results suggested that NO/cGMP-dependent mechanism might be involved in toluene-induced locomotor activity in rats.     

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

Rationale The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signal transduction pathway has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phosphodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. Objectives We examined whether treatment with sildenafil citrate, a PDE type 5 inhibitor, would attenuate a learning impairment induced by inhibition of NO synthase [60 mg/kg N ^ω-nitro-l-arginine methyl ester (l-NAME), i.p.]. Methods Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and, on the next day, received 15 training trials in a 14-unit T-maze, a task that has been shown to be sensitive to aging and impairment of central NO signaling systems. Combined treatments of l-NAME or saline and sildenafil (1.0, 1.5, 3.0, or 4.5 mg/kg, i.p.) or vehicle were given 30 and 15 min before training, respectively. Behavioral measures of performance included entries into incorrect maze sections (errors), run time from start to goal (latency), shock frequency, and shock duration. Results Statistical analysis revealed that l-NAME impaired maze performance and that sildenafil (1.5 mg/kg) significantly attenuated this impairment. Control experiments revealed that administration of l-NAME alone did not significantly increase latencies in a one-way active avoidance test and that different doses of sildenafil alone did not significantly alter complex maze performance. Conclusions The results indicate that sildenafil may improve learning by modulating NO–cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease. M. Jimenez and D. Sierra-Mercado, Jr., were supported by Minority Access to Research Careers grants NIGMS 08253 and NIGMS 07717.     

Inhibitory effects of MPEP,an mGluR5 antagonist,and memantine,an <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate receptor antagonist,on morphine antinociceptive tolerance in mice

Abstract Rationale. Inhibition of N-methyl-D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. Objective. In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. Methods. Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose–response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. Results. MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. Conclusions. The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance. Electronic Publication     

Attenuation of some signs of opioid withdrawal by inhibitors of nitric oxide synthase

Effects of nitric oxide synthase (NOS) inhibitors (l-N ^G-nitroarginine,l-N ^G-nitroarginine methyl ester) on precipitated opioid withdrawal were studied in morphine-dependent rats given naloxone, in order to assess the involvement of nitric oxide (NO) in opioid dependence.l-N ^G-Nitroarginine (7.5 mg/kg, IP, 1 h before naloxone or b.i.d. on days 4–7 of an 8-day morphine treatment) reduced wet dog shakes and weight loss; when given by osmotic pumps (15 mg/kg per day), the drug reduced wet dog shakes but not weight loss.l-N ^G-Nitroarginine methyl ester (60 mg/kg, 1 h before naloxone) also reduced wet dog shakes and weight loss. The results indicate that NOS inhibitors warrant further study as potential treatment of the opioid withdrawal syndrome.Abstracts were presented at meetings of the Society for Neuroscience in New Orleans, La., November 10–15, 1991 and of the American Society for Pharmacology and Experimental Therapeutics in Orlando, Fla., August 10–18, 1992     

Dopamine and nitric oxide interaction on the modulation of prepulse inhibition of the acoustic startle response in the Wistar rat

Rationale The nitric oxide (NO)–arginine pathway is intimately connected to the release of dopamine (DA), a neurotransmitter system that may be dysfunctional in schizophrenia. Both schizophrenic patients and rats treated with DA agonists present deficits in sensorimotor gating measured by prepulse inhibition (PPI). Objective Our aim was to investigate the interaction between a NO synthase inhibitor, N ^G-nitro-l-arginine (l-NOARG), and the DA agonists, amphetamine (Amph), apomorphine (Apo), bromocriptine (BRC), quinpirole (QNP) and SKF38393, on the modulation of the PPI. Methods Male Wistar rats received two injections of either l-NOARG (40 mg/kg, i.p.) or saline, 1 h before the test, and the DA agonists or vehicle. Testing began 5 min after treatment with Amph (2 mg/kg, i.p.), Apo (0.5 mg/kg, s.c.) or QNP (0.3 mg/kg and 1.0 mg/kg, s.c.), 120 min after BRC (1 and 40 mg/kg, i.p.) and 15 min after SKF38393 (10 mg/kg, s.c.). The PPI test consisted of 60 presentations divided into pulse (100 dB), prepulse (65, 70, 75 and/or 80 dB) and prepulse + pulse. Results l-NOARG prevented the PPI disruption caused by Amph (2 mg/kg). Apo, QNP and BRC disrupted PPI, but these effects were not significantly changed by l-NOARG. SKF38393 had no significant effect on PPI whether or not preceded by l-NOARG. Conclusions Our findings show that l-NOARG interacted with Amph, an indirect DA agonist, but not with the direct DA agonists on PPI, suggesting that NO is involved on the dopaminergic modulation of sensorimotor gating, probably by a presynaptic mechanism.     

Comparison of behavioral and cardiovascular effects of l-DOPA and 5-HTP in conscious dogs

Moderate doses of l-DOPA (30–40 mg/kg) alone produced depressant effects, emesis and a mild hypertensive response in dogs. These depressant effects included decreased alertness, reduced response to overt stimuli such as whistling or sharp noises, reduced response to handling and a degree of flaccidity. Haloperidol completely blocked the behavioral and emetic effects of l-DOPA and, in most cases, significantly reduced the hypertensive response. Methysergide prevented the depressive effects and significantly attenuated emesis but had variable effect on the hypertensive response of l-DOPA. HMD and Ro 4-4062, in doses which selectively inhibit peripheral decarboxylase, completely blocked most of the behavioral effects, markedly attenuated emesis and prevented or reduced the hypertensive response, of l-DOPA. HMD, in addition, converted the hypertensive response of l-DOPA to a hypotensive response. dl-Parachlorophenylalanine completely blocked the behavioral effects and significantly reduced the cardiovascular effect of l-DOPA but had no effect on emesis induced by l-DOPA. dl-5-HTP, in contrast to l-DOPA, produced behavioral excitation in the dogs. It also produced a hypertensive response. Haloperidol had no significnat effect on the behavioral responses but significantly reduced the cardiovascular response produced by dl-5-HTP. Methysergide, similarly, had no significant effect on the behavioral responses of dl-5-HTP but had variable effects on the hypertensive response. Ro 4-4602 and HMD also had no effect on the behavioral and cardiovascular responses due to dl-5-HTP. l-DOPA failed to prevent the behavioral effects of 5-HTP. 5-HTP completely blocked or significantly attenuated the emetic response produced by l-DOPA although there was no significant change in the blood pressure when compared with controls.This work was supported by USPHS Grant MH 12383.     

Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats

Rationale Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists.Objective The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle.Methods Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03–0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1–10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075–0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1–3 mg/kg, s.c.) and MRZ 2/621 (0.3–10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3–10 mg/kg, i.p.).Results In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED₅₀=0.67 mg/kg) and MRZ 2/621 (ED₅₀=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose–response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding.Conclusions NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.     

丁基苯酞对局灶性脑缺血大鼠软脑膜微循环障碍的影响

目的：观察消旋、左旋及右旋丁基苯酞（dl-,l-,d-3-n-butylphthalide,dl-,l-,d-NBP）对局灶性脑缺血大鼠软脑膜微循环障碍的影响。方法：用插线法造成大鼠局灶性脑缺血模型,并用体外显微摄像技术及微循环图象处理系统观察大鼠软脑膜微动脉管径及红细胞流速的变化。结果：dl-,l-和d-NBP对正常大鼠脑微动脉管径无明显影响,MCAO术前1 h预防给药,dl-,l-NBP和尼莫地平可明显增加局灶性脑缺血大鼠软脑膜微动脉管径及血流速度,而d-NBP则加重软脑膜微循环障碍。MCAO术后20 min治疗给药,dl-和l-NBP仍可明显逆转局灶性脑缺血大鼠软脑膜微循环障碍,而d-NBP及尼莫地平作用不明显。结论：改善脑微循环状态是 dl-和l-NBP发挥抗脑缺血作用的重要药理机制之一。     

Restoration of brainmyo-inositol levels in rats increases latency to lithium-pilocarpine seizures

Lithium pretreatment in rats potentiates the epileptogenic effects of pilocarpine and other cholinergic agonists. In order to determine if this effect of lithium could be reversed bymyo-inositol, rats were pretreated with intracerebroventricular (ICV) injections ofmyo-inositol, artificial CSF orl-chiro-inositol. Lithium chloride, 3 meq/kg was administered intraperitoneally 20–24 h prior to the subcutaneous injection of pilocarpine 20 or 30 mg/kg. In both experiments,myo-inositol significantly prolonged the latency to the appearance of clonic seizures and lowered the pilocarpine seizure score.myo-Inositol prevented the development of clonic seizures in 50% of the rats receiving pilocarpine, 20 mg/kg. The levels of corticalmyo-inositol in rats injected withmyo-inositol were approximately double those of the CSF andl-chiro-inositol groups.     

Cocaine-induced reinstatement in rats: evidence for a critical role of cocaine stimulus properties

Rationale While the N-methyl-d-aspartate (NMDA) glutamate receptor has been strongly implicated in chronic opiate dependence, relatively few studies have examined the effects of NMDA receptor antagonists on withdrawal from acute opiate exposure. Objectives The current study examined the effects of memantine, a well-tolerated NMDA receptor antagonist, on acute opiate dependence as assessed by elevations in rodent startle responding (i.e., “withdrawal-potentiated startle”) and increased pain sensitivity (i.e., hyperalgesia). Results Administration of memantine either attenuated (5 mg/kg) or blocked (10 mg/kg) the expression of withdrawal-potentiated startle during naloxone (2.5 mg/kg)-precipitated withdrawal from a single dose of morphine sulfate (10 mg/kg). Pre-treatment with the NMDA receptor antagonist also inhibited the exacerbation of withdrawal-potentiated startle across repeated acute opiate exposures. Memantine blocked the expression of acute dependence, but was less effective in inhibiting its escalation, when hyperalgesia was used as a measure of withdrawal. These doses of memantine did not affect startle responding or nociception in otherwise drug-free animals. Data from additional control groups indicated that the effects of memantine on the expression of withdrawal were not influenced by nonspecific interactions between the NMDA antagonist and either morphine or naloxone. Conclusions These findings suggest that the NMDA receptor may play a key role in the earliest stages of opiate dependence and provide further evidence that memantine may be useful for the treatment of opiate withdrawal.     

Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal

Previously, we demonstrated that two nonselective inhibitors of nitric oxide synthase (NOS),l-N ^G-nitroarginine (l-NNA) andl-N ^G-nitroarginine methyl ester (l-NAME), reduced some signs of morphine withdrawal in rats. The present work extended these studies to include 7-nitroindazole (7-NI), an inhibitor specific for cerebral NOS, andN(5)-(1-iminoethyl)-l-ornithine (l-NIO), a potent inhibitor of endothelial NOS. Behavioral effects of these four NOS inhibitors and clonidine, an ₂-adrenoceptor, agonist, on morphine withdrawal in rats were assessed. Rats received one 75-mg morphine pellet subcutaneously (SC). Three days later, NOS inhibitors were administered IP 1 h before withdrawal was precipitated with naloxone (0.5 mg/kg, SC) and scored. 7-NI,l-NIO,l-NAME andl-NNA produced dose-related decreases in weight loss, diarrhea, wet dog shakes and grooming. 7-NI also reduced mastication, salivation and genital effects. Clonidine produced effects similar to 7-NI. In awake, morphine-naive and morphine-dependent rats not subjected to withdrawal, 7-NI was the only NOS inhibitor that did not increase blood pressure. Because 7-NI attenuated more signs of opioid withdrawal thanl-NNA,l-NAME orl-NIO without causing hypertension, 7-NI appears to warrant further testing as a potential candidate for human use.Abstracts were presented at the annual meetings of the College on Problems of Drug Dependence, West Palm Beach, Fla., 18–23, June 1994; International Narcotics Research Conference, North Falmouth, Cape Cod, Mass., 16–21, July 1994; and a Satellite Symposium to IUPHAR, Montreal, Canada, 22–24, July 1994.     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.     

Nitric oxide is involved in the memory facilitation induced by spermidine in rats

Rationale Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-d-aspartate receptor functions, which has been reported to facilitate memory formation.Objectives In the current study, we investigated the involvement of nitric oxide in the facilitatory effect of SPD on the memory of adult male Wistar rats in the inhibitory avoidance task.Results The coadministration of the nonspecific NOS inhibitor N ^G nitro-l-arginine methyl ester (l-NAME) (0.1 nmol, intrahippocampus) with spermidine (0.2 nmol), immediately after training, prevented the memory improvement caused by spermidine in the avoidance inhibitory task. Spermidine increased nitrite and nitrate levels (NO_X) in the hippocampus 30 min after its administration, and l-NAME coinjection prevented the stimulatory effect of spermidine on NO_X levels. The systemic injection of 7-nitroindazole (30 mg/kg, i.p.), 30 min before training, impaired memory and did not prevent spermidine-induced increase of NO_X levels in the hippocampus.Conclusions These results suggest that memory enhancement by spermidine is prevented by the nonspecific nitric oxide synthase inhibitor l-NAME.     

Influence of l-3-methoxytyrosine on monoamine synthesis in rat brain

Summary Rats were injected i.p. with l-3-methoxytyrosine, 100 or 300 mg/kg. One h later brain, liver, heart and blood plama were analyzed for catecholamines and their precursors. In brain Dopa as well as dopamine and noradrenaline levels were unchanged, while demethylation of l-3-methoxytyrosine might have occurred in peripheral organs since Dopa levels in liver and dopamine in heart were elevated. 3-Methoxytyramine could not be detected in brain and liver after treatment with l-3-methoxytyrosine.Monoamine synthesis in vivo was measured in whole brain by determining the accumulation of Dopa and 5-hydroxytryptophan 30 min after the i.p. injection of NSD 1015 (3-hydroxybenzylhydrazine HCl, 100 mg/kg), an inhibitor of the aromatic amino acid decarboxylase. l-3-Methoxytyrosine attenuated the formation of Dopa and 5-hydroxytryptophan by about 25% in brain tissue. The effect was paralleled by a decrease in the brain concentration of tryptophan.     

Differences between (+)- and (−)-amphetamine in effects on locomotor activity and l-dopa potentiating action in mice

Summary The l-Dopa-potentiating effects of the two optical isomers of amphetamine, as well as the effects of their own, were investigated in mice, using locomotor activity as test parameter. The study was performed in three steps. First, the time-course were studied for the effects of (+)- and (–)-amphetamine and l-Dopa. Second, dose-response relationships were established for the amphetamine enantiomers. Third, the l-Dopa-potentiating effects, of a few, selected doses of the amphetamine isomers were investigated by establishing dose-response curves for l-Dopa with and without the amphetamines. All animals given l-Dopa were pretreated with an inhibitor of extracerebral aromatic amino acid decarboyxlase. (+)-Amphetamine, 0.5–8 mg/kg, caused a dose-dependent stimulation of locomotoractivity, whereas (–)-amphetamine, 1–4 mg/kg, caused a dose-dependent depression. Doses higher than 8 mg/kg of the laevo-isomer caused stimulation of the activity. (+)-Amphetamine, 0.25 mg/kg, and (–)-amphetamine, 0.5 mg/kg, i.e. doses without any effect on locomotor activity of their own, caused virtually the same shift to the left of the dose-response curve for l-Dopa. (–)-Amphetamine, 4 mg/kg which per se caused depression of locomotor activity, caused a marked potentiation of the l-Dopa-induced stimulation of motor activity. Thus, there does not exist a close correlation between the l-Dopa-potentiating action of the amphetamines and their stimulating properties per se.     

左旋丁苯酞对脑低灌注大鼠学习记忆及脑β-淀粉样肽含量的影响

目的：以老龄大鼠为研究对象,观察左旋丁苯酞（L－3－n—Butylphthalide,1－NBP）对脑低灌注大鼠学习记忆的改善作用,并研究其皮质及海马β-淀粉样肽（Aβ1-42）水平变化。方法：永久性结扎老龄大鼠双侧颈总动脉3个月,制备脑低灌注模型。实验分4组：假手术组、溶剂对照组、30mg·kg^－11-NBP和120mg·kg^－11—NBP组。1—NBP组连续给予1－NBP45d后,用Morris水迷宫检测大鼠的空间学习和记忆以及保存记忆的能力。同时,取大鼠脑皮质及海马组织,用ELISA法检测Aβ1－42含量,以探讨1．NBP改善认识功能作用机制。结果：1-NBP可以显著缩短脑低灌注大鼠找到安全台的潜伏期,并明显增加脑低灌注大鼠在目标象限活动时间的百分比,明显降低大鼠皮质及海马AIM42含量。结论：1－NBP能改善脑低灌注大鼠的学习记忆缺陷,减少皮质及海马Aβ1－42的水平,这可能是改善脑低灌注大鼠认知功能的重要机制之一。     

Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: hypertension,cardiac hypertrophy and renal insufficiency

Inhibition of the angiotensin converting enzyme (ACE) with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by N^G-nitro-l-arginine methyl ester (l-NAME). Chronic treatment with l-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 ± 16 mmHg) as compared to controls (155+4 mmHg). Animals receiving simultaneously l-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56+0.73 ml·kg^–1·min^–1) and renal plasma flow (RPF: 6.93±1.70ml·kg^–1·min^–1) as compared to control (GFR: 7.29±0.69, RPF: 21.36±2.33ml·kg^–1·min^–1). Addition of ramipril prevented l-NAME-induced reduction in GFR and renal plasma flow. l-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with l-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischaemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased. Coadministration of ramipril reversed these effects. l-NAME treatment reduced the cyclic GMP content in urine and renal arteries, and was not changed by additional ramipril-treatment. In the kidney hyalinosis of arterioles and of glomerular capillaries, as well as mesangial expansion and tubular atrophies seen after long-term inhibition of NO synthase were reduced by coadministration of ramipril. In conclusion, long-term ACE inhibition by ramipril prevented l-NAME-induced hypertension and cardiac hypertrophy, and attenuated functional and morphological changes in the kidneys. In addition, cardiac-dynamic and -metabolic deterioration induced by L-NAME was normalised by co-treatment with ramipril. Correspondence to: Max Hropot at the above address     

Cognitive dysfunction induced by sequential injection of amyloid-beta and ibotenate into the bilateral hippocampus; protection by memantine and MK-801

Aggregated 40-residue amyloid-beta peptide (beta40, 4 microg/microl), and 2 days later, ibotenate (NMDA receptor agonist, 0.3 microg/0.5 microl), were bilaterally injected into the hippocampus of rats. Five to six weeks after the beta40 injection, the rats showed learning deficits in the Morris water maze task and neuronal damage in the hippocampus, although the injection of beta40 or ibotenate alone did not result in cognitive deficits and hippocampal damage. Memantine (10, 20 mg/kg/day s.c. infusion for 6 weeks starting 24 h before the beta40 injection) significantly prevented learning deficits as measured for 4 days from 5 weeks after the beta40 injection, while a lower dose of memantine (5 mg/kg/day) and MK-801 (0.312, 0.624 mg/kg/day) did not have inhibitory effects on the learning deficits. The neuronal damage in the hippocampus, assessed as an elevation of the levels of the peripheral-type benzodiazepine-binding site (a gliosis marker for neuronal damage) produced by sequential intra-hippocampal injections of beta40 and ibotenate, at 6 weeks (39 days) after the beta40 injection, was significantly attenuated by memantine (10, 20 mg/kg/day) and MK-801 (0.624 mg/kg/day). These protective effects were also confirmed by histochemical examination (Cresyl violet staining of brain slices). In naive rats, MK-801 produced a significant learning impairment in the water maze task at a dose of 0.624 mg/kg/day, while memantine (20 mg/kg/day s.c. infusion) did not, although the beta40 plus ibotenate-induced hippocampal damage was lessened by both treatments. These results suggest that memantine and MK-801 exert protective effects on progressive neuronal damage, but that only memantine prevents memory impairment in hippocampal-lesioned rats, and that memantine may be a beneficial agent for the treatment of progressive cognitive dysfunction including Alzheimer's disease-type dementia.