Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.     

Enhanced susceptibility to the GABA antagonist pentylenetetrazole during the latent period following a pilocarpine-induced status epilepticus in rats

A variety of acute brain insults bear the risk of subsequent development of chronic epilepsy. Enhanced understanding of the brain alterations underlying this process may ultimately lead to interventions that prevent, interrupt or reverse epileptogenesis in people at risk. Various interventions have been evaluated in rat models of symptomatic epilepsy, in which epileptogenesis was induced by status epilepticus (SE) or traumatic brain injury (TBI). Paradoxically, recent data indicated that administration of proconvulsant drugs after TBI or SE exerts antiepileptogenic or disease-modifying effects, although epilepsy is often considered to represent a decrease in seizure threshold. Surprisingly, to our knowledge, it is not known whether alterations in seizure threshold occur during the latent period following SE. This prompted us to study seizure threshold during and after the latent period following SE induced by lithium/pilocarpine in rats. Timed intravenous infusion of the GABA(A) receptor antagonist pentylenetetrazole (PTZ) was used for this purpose. The duration of the latent period was determined by continuous video/EEG monitoring. Compared to control seizure threshold determined before SE, threshold significantly decreased two days after SE, but returned to pre-SE control thereafter. Moreover, the duration of PTZ-induced seizures was significantly increased throughout the latent period, which ranged from 6 to 10 days after SE. This increased susceptibility to PTZ likely reflects the complex alterations in GABA-mediated transmission that occur during the latent period following SE. The data will allow developing dosing regimens for evaluation of whether treatment with subconvulsant doses of PTZ during the latent period affects the development of epilepsy.     

Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats

Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. One promising candidate in this respect is valproic acid (VPA), a widely used AED that has been reported to exert neuroprotective activity in a number of in vitro and in vivo models. The present study investigated whether VPA reduces brain damage and improves functional outcome in a rat model of post-SE epilepsy. A self-sustaining SE was induced by prolonged electrical stimulation of the basal amygdala via a depth electrode. SE was terminated after 4 h by diazepam, immediately followed by onset of treatment with VPA. VPA was injected i.p. at a bolus dose of 400 mg/kg, followed by three times daily administration of 200 mg/kg for 4 weeks. A control group received vehicle instead of VPA after SE. Spontaneous seizures were recorded in all rats of both groups following termination of treatment, without significant inter-group difference in seizure frequency or severity. However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the dentate hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.     

Attenuation of cocaine-seeking behaviour by the AMPA/kainate receptor antagonist CNQX in rats

Abstract Rationale. It has been suggested previously that conditioned effects on drug-seeking behaviour are in part mediated through glutamatergic neurotransmission. Objectives. To optimise a second-order schedule of IV cocaine reinforcement in Wistar rats and investigate the effects of the systemic AMPA/kainate receptor antagonist CNQX on cocaine-seeking behaviour under this schedule. Methods. Free-feeding Wistar rats were trained to respond for an IV cocaine infusion (0.25 mg/infusion) under a FI15 min(FR7:S) schedule, whereby the completion of FR7 responses led to the presentation of a conditioned stimulus (CS). After two 15-min fixed intervals, rats were allowed to respond for cocaine under an FR4(FR7:S) second-order schedule for another 120 min. After acquisition of stable responding, the cocaine unit dose was increased to 0.50 mg/infusion. The effects of CNQX (0, 0.75, 1.5, and 3 mg/kg IP) on cocaine seeking were then examined using a within-subjects design. Results. Increasing the cocaine unit dose increased responding during the first and second intervals, with a decrease in the latency to the first CS. CNQX decreased the number of cocaine responses in a dose-dependent manner during the first 15-min cocaine-free interval, but did not affect cocaine responding during either the second interval or the latter part of the session under the FR4(FR7:S) schedule. In the locomotor activity test, reductions in rearing were produced by higher CNQX doses than those that attenuated significantly responding during the first fixed interval. Conclusions. These results suggest that AMPA/kainate receptors are involved in mediation of cocaine-seeking behaviour controlled partly by cocaine-associated cues. Electronic Publication     

Naringin protects against kainic acid-induced status epilepticus in rats: evidence for an antioxidant, anti-inflammatory and neuroprotective intervention

The effect of naringin, a bioflavanoid, with potent antioxidant activity was studied on kainic acid (KA)-induced seizures, cognitive deficit and oxidative stress. Rats were administered KA (10 mg/kg intraperitoneally (i.p.)) and observed for behavioral changes and incidence and latency of convulsions over 4 h. The rats were thereafter sacrificed and oxidative stress parameters like malondialdehyde (MDA) and glutathione (GSH) were estimated in the brain. The level of proinflammatory cytokine, tumor necrosis factor (TNF)-α was also determined in the rat brain. It was observed that pretreatment with naringin (20, 40, 80 mg/kg, i.p.) significantly (p<0.001) increased the latency of seizures as compared to the vehicle treated-KA group. Naringin (40, 80 mg/kg) also significantly prevented the increase in MDA and fall in GSH levels due to KA. In addition, naringin dose-dependently attenuated the KA-induced increase in the TNF-α levels of brain. The pretreatment with naringin also significantly increased retention latency in the passive avoidance task. This shows that naringin reduced the cognitive deficit induced by KA. The results of our study suggest that naringin has therapeutic potential since it suppresses KA-induced seizures, cognitive impairment and oxidative stress in the brain. These neuroprotective effects are a result of its antioxidant and anti-inflammatory activity.     

The neuroprotective effects of the decahydroisoquinoline, LY 215490; a novel AMPA antagonist in focal ischaemia

LY 215490 (3 RS,4aRS,6RS,8aRS)-6-[2-(1(2)H- tetrazole- 5-yl)ethyl]decahydroisoquinoline -3-carboxylic acid), a novel, selective, competitive and systemically active AMPA receptor antagonist was tested as a neuroprotective agent against focal ischaemia in a model of permanent MCA occlusion in the rat. LY 215490 was administered at a dose of 10, 30 or 100 mg/kg 30 min prior to and post-MCA occlusion. The animals were allowed to survive for 24 hr, following which time the brains were processed for volumetric analysis of the infarct size. The low dose of LY 215490 was not effective against the infarct volume in the hemisphere, cortex or caudate. The 2 × 30 mg/kg dose of LY 215490 resulted in 25 and 31% protection against the volume of hemispheric and cortical ischaemic damage, respectively. The highest dose of LY 215490 resulted in a reduced neuroprotective effect with 23 and 27% protection against the volume of hemispheric and cortical ischaemic damage, respectively. The slightly reduced neuroprotective effect of the highest dosing regimen may be due to the respiratory problems seen with this dose. Neither of the two neuroprotective doses of LY 215490 produced any reduction in the volume of caudate damage which represents the core of the infarct.     

奥氮平联合丙戊酸钠治疗难治性癫痫持续状态的临床效果观察

目的 观察奥氮平联合丙戊酸钠治疗难治性癫痫持续状态的临床效果。方法 采用回顾性、随机对照研究方法,将2015年2月—2017年9月在遂宁市中心医院诊治的难治性癫痫持续状态患者190例分为观察组与对照组各95例,对照组给予丙戊酸钠治疗,初剂量为5~10 mg/（kg·d）,然后每周增加剂量5~10 mg/（kg·d）,持续增加到剂量为20~30 mg/（kg·d）后进行维持治疗。观察组在对照组治疗的基础上给予奥氮平6 mg治疗,1次/d。两组都治疗观察4周。比较两组近期疗效、不良反应及认知功能情况。结果 观察组与对照组的总有效率分别为98.9%和88.4%,观察组明显高于对照组,差异有统计学意义（P<0.05）。观察组的不良反应发生率4.2%与对照组（6.3%）无统计学差异。两组治疗后的简易精神状态检查量表（MMSE）评分均明显高于治疗前,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组的MMSE评分明显高于对照组,组间差异有统计学意义（P<0.05）。结论 奥氮平联合丙戊酸钠治疗难治性癫痫持续状态能提高治疗效果,不会增加不良反应的发生,能促进患者认知功能的改善,有很好的应用效果。     

Hypophagic effect of the angiotensin AT1 receptor antagonist irbesartan in rats

Recent experimental and clinical studies report beneficial metabolic effects of antihypertensive drugs interfering with angiotensin. Antagonists at the angiotensin AT(1) receptor can reduce blood glucose and triglyceride levels. So far, there is little evidence, however, that angiotensin AT(1) receptor antagonists can also affect food intake. Particularly unknown is if drugs of this class can have acute effects on short term feeding. To address this issue, the angiotensin AT(1) receptor antagonist irbesartan was studied in a one-hour feeding paradigm in rats. In this study, irbesartan was investigated in comparison with fenfluramine, an established satiating drug, and the angiotensin converting enzyme (ACE) inhibitor captopril. We found a significant reduction of one-hour food intake following 100-200 mg/kg (i.p.) irbesartan. The ACE inhibitor captopril (25-100 mg/kg i.p.) remained without effect on food intake and fenfluramine showed the expected hypophagic action starting at 1 mg/kg (i.p.). The hypophagic effect of irbesartan could not be attributed to sedation or any gross effect on motor activity as determined both upon feeding and independent activity experiments. Fenfluramine (1 mg/kg) and irbesartan (100 mg/kg) did not reduce the latency to feed, but similarly reduced the eating rate at the beginning of the test meal. In conclusion, the present study demonstrates a hypophagic effect of the angiotensin AT(1) receptor antagonist irbesartan that cannot be attributed to sedation or antidipsic effects of the drug.     

Asymmetry in enhanced neurogenesis in the rostral dentate gyrus following kainic acid-induced status epilepticus in adult rats

Neurogenesis in the suprapyramidal and infrapyramidal blades of the rostral dentate gyrus was investigated following kainic acid (KA)-induced status epilepticus (SE) in adult rats. Rats were injected with KA (14 mg/kg, i.p.) or saline, with convulsions terminated by an intraperitoneal injection of diazepam. Five days after the induction of SE, the rats were injected with 5-bromo-2-deoxyuridine-5-monophosphate (BrdU; 75 mg/kg, i.p.), a marker of cell division. One day after the BrdU injection, the numbers of BrdU-labeled cells in the supra- and infrapyramidal blades were significantly higher in the KA-injected rats compared to the saline-injected rats. In the saline-injected rats, the number of BrdU-labeled cells in the infrapyramidal blade was greater than in the suprapyramidal blade. Twenty-eight days after the BrdU injection, the number of BrdU-labeled cells remained significantly higher in the KA-injected rats than the saline-injected rats, but only in the infrapyramidal blade. In addition, when the extent of cell death was examined with Fluoro-Jade B (a marker of dead and dying cells) 3 days after the induction of SE, degenerating cells were more numerous in the infrapyramidal blade than in the suprapyramidal blade. Our results suggest that there is an asymmetry of neurogenesis and cell death in the rostral dentate gyrus of rats following KA-induced SE.     

Design of a high-affinity competitive antagonist of the vanilloid receptor selective for the calcium entry-linked receptor population

We describe the synthesis and characterization of N-(4-chlorobenzyl) -N'-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea (IBTU), a novel antagonist of the vanilloid receptor 1 (TRPV1 or VR1). IBTU competitively inhibited 45Ca2+ uptake into CHO cells heterologously expressing rat TRPV1, whether induced by capsaicin or resiniferatoxin (Ki = 99 +/- 23 and 93 +/- 34 nM, respectively). IBTU was thus somewhat more potent (5-fold) than capsazepine. In contrast to its antagonism of vanilloid-induced calcium uptake, IBTU (30 microM) inhibited [3H]resiniferatoxin binding to TRPV1 by less than 10%. We hypothesize that these dramatically distinct potencies reflect different fractions of TRPV1 in this system: namely, a minor plasma membrane fraction controlling 45Ca2+ uptake, and the predominant intracellular fraction that dominates the [3H]resiniferatoxin binding measurements. Intracellular Ca2+ imaging supports this explanation. IBTU antagonized the elevation in intracellular Ca2+ in response to 50 nM capsaicin with an IC50 of 106 +/- 35 nM. Likewise, 600 nM IBTU was able to antagonize the elevation in intracellular Ca2+ in response to 100 pM resiniferatoxin in the presence of normal (1.8 mM) extracellular Ca2+, where the increase in intracellular calcium reflects calcium influx. In contrast, in the absence of extracellular Ca2+, where in this system resiniferatoxin induces a modest increase in calcium from intracellular stores, IBTU was unable to block the response to resiniferatoxin, although the TRPV1 antagonist 5-iodoresiniferatoxin was able to do so. In summary, IBTU is a novel, potent TRPV1 antagonist with marked selectivity between subpopulations of TRPV1 and may permit the function of these distinct pools to be explored and potentially exploited.     

Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease

Excitatory neurotransmission in the CNS depends heavily upon α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors. Derangements in AMPA receptor mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Recently, drugs that positively modulate AMPA receptors have been identified, having differential effects upon certain AMPA receptor subunits and different effects upon physiological properties of AMPA receptors. These drugs facilitate AMPA receptor mediated processes and may have beneficial therapeutic effects. For example, certain AMPA modulators facilitate long-term potentiation, which is considered a cellular mechanism that may be important for memory storage and they also facilitate memory encoding in behavioural experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer’s disease (AD). However, AMPA receptor mediated excitotoxicity may occur with excessive AMPA receptor activation which occurs in seizures or ischaemia and positive AMPA modulators could promote neuronal injury in those conditions. Ultimately, the clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity. Currently available drugs have provided significant insight into the physiology and structural determinants of important AMPA receptor properties and some insight into potential clinical uses as well as potential dangers of such drugs.     

Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction

Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V(1A) and V(2) receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V(1A) receptors and plays a major role in retaining free water through vasopressin V(2) receptors in this model of congestive heart failure. Additionally, conivaptan, with its dual vasopressin V(1A) and V(2) receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.     

依达拉奉对大鼠癫痫持续状态后脑自由基代谢及海马神经元凋亡的影响

目的观察依达拉奉对大鼠癫痫持续状态后脑内自由基及海马神经元凋亡的影响及可能机制。方法采用氯化锂-匹罗卡品大鼠癫痫持续状态模型,成年雄性Wistar大鼠54只随机分为实验组48只和对照组6只,实验组分为模型组、依达拉奉治疗组,每组按照时间点分为4个亚组(12、24、72 h,7 d)。化学比色法测定脑组织匀浆中超氧化物歧化酶(SOD)活性、丙二醛(MDA)的含量,免疫组织化学法检测大鼠脑组织c-fos蛋白表达。结果与对照组相比,模型组的SOD活性在12 h开始下降,72 h时最低(P<0.01),7 d时恢复正常;依达拉奉治疗组与之趋势相同,但各时间点均高于模型组。模型组的MDA含量和大鼠脑组织的c-fos蛋白表达在各时间点均高于对照组(P<0.05);依达拉奉治疗组与之趋势相同,但在24、72 h低于模型组(P<0.05)。结论依达拉奉可以清除自由基,减少海马神经元的凋亡,对癫痫持续状态后的脑损伤有一定的保护作用。     

Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease

Excitatory neurotransmission in the CNS depends heavily upon alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors. Derangements in AMPA receptor mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Recently, drugs that positively modulate AMPA receptors have been identified, having differential effects upon certain AMPA receptor subunits and different effects upon physiological properties of AMPA receptors. These drugs facilitate AMPA receptor mediated processes and may have beneficial therapeutic effects. For example, certain AMPA modulators facilitate long-term potentiation, which is considered a cellular mechanism that may be important for memory storage and they also facilitate memory encoding in behavioural experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease (AD). However, AMPA receptor mediated excitotoxicity may occur with excessive AMPA receptor activation which occurs in seizures or ischaemia and positive AMPA modulators could promote neuronal injury in those conditions. Ultimately, the clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity. Currently available drugs have provided significant insight into the physiology and structural determinants of important AMPA receptor properties and some insight into potential clinical uses as well as potential dangers of such drugs.     

Therapeutic potential of positive AMPA receptor modulators in the treatment of neuropsychiatric disorders

Drugs that potentiate the activity of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor cause a complex cascade of consequences in experimental models, ranging from enhancement of long-term potentiation to induction of neurotrophic factors. Animal studies characterising the pharmacological and behavioural effects of these substances have provided the rationale for several initial attempts to use these drugs in neuropsychiatric clinical settings. Applications in schizophrenia, Alzheimer's disease and mild cognitive impairment have been initiated. Other trials with these compounds include the treatment of Fragile X syndrome, and possible future applications may be in the field of Parkinson's disease. The literature published to date is limited mostly to small phase I or II trials, so there is no conclusive evidence for or against the use of these drugs. Substantial questions remain concerning which compounds to use, in what dose, for what condition and for how long.     

Therapeutic potency of pharmacological adenosine receptor agonist/antagonist in angiogenesis,current status and perspectives

Objectives

Adenosine concentration significantly increases in tumour microenvironment contributing to tumorigenic processes including cell proliferation, survival, invasion and of special interest in this review angiogenesis.

Key findings

This review summarizes the role of pharmacological adenosine receptor agonist and antagonist in regulating angiogenesis for a better understanding and hence a better management of angiogenesis‐associated disorders.

Summary

Depending upon the pharmacological characteristics of adenosine receptor subtypes, adenosine elicits anti‐ or pro‐angiogenic responses in stimulated cells. Inhibition of the stimulatory effect of adenosine signalling on angiogenesis using specific pharmacological adenosine receptor agonist, and antagonist is a potentially novel strategy to suppress angiogenesis in tumours.

     

组胺受体拮抗剂联合白三烯受体拮抗剂治疗过敏性鼻炎的疗效观察

目的 探讨H1组胺受体拮抗剂(H1RAs)联合白三烯受体拮抗剂(LTRAs)治疗过敏性鼻炎(AR)的临床疗效.方法 AR患者84例,采用随机数字表法分为观察组与对照组,各42例.对照组单用H1RAs——盐酸氮卓斯汀治疗,观察组在对照组基础上加用LTRAs——孟鲁司特钠治疗,对比两组的临床疗效,治疗前后评价鼻炎症状评分,检测血清微量元素、嗜酸性粒细胞阳离子蛋白(ECP)、特异性免疫球蛋白E(sIgE)及炎性因子水平.结果 观察组的总有效率为100.00％,显著高于对照组的88.10％(P<0.05);治疗后观察组的鼻炎症状评分显著低于对照组(P<0.05);治疗后观察组的血清sIgE、ECP、白细胞介素(IL)-4、IL-6、IL-8、Cu均显著低于对照组,IL-10、γ-干扰素(INF-γ)、Zn、Mn显著高于对照组(P<0.05).结论 H1RAs联合LTRAs治疗AR能够提高临床疗效、改善鼻炎症状,其机制可能与调节血清微量元素及sIgE、ECP水平、抗炎性反应有关.     

Hydroalcoholic extract of Emblica officinalis protects against kainic acid-induced status epilepticus in rats: Evidence for an antioxidant,anti-inflammatory,and neuroprotective intervention

Context: Emblica officinalis (Euphorbiaceae), commonly known as amla, is traditionally used for central nervous system (CNS) disorders.

Objective: In the present study, the effect of standardized hydroalcoholic extract of E. officinalis fruit (HAEEO), an Indian medicinal plant with potent antioxidant activity, was studied against kainic acid (KA)-induced seizures, cognitive deficits and on markers of oxidative stress.

Materials and methods: Rats were administered KA (10?mg/kg, i.p.) and observed for behavioral changes, incidence, and latency of convulsions over 4?h. The rats were thereafter sacrificed for estimation of oxidative stress parameters: thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH). The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) was also determined in the rat brain.

Results: Pretreatment with HAEEO (500 and 700?mg/kg, i.p.) significantly (P?<?0.001) increased the latency of seizures as compared with the vehicle-treated KA group. HAEEO significantly prevented the increase in TBARS levels and ameliorated the fall in GSH. Furthermore, HAEEO dose-dependently attenuated the KA-induced increase in the TNF-α level in the brain. HAEEO also significantly improved the cognitive deficit induced by KA, as evidenced by increased latency in passive avoidance task.

Discussion and conclusion: HAEEO at the dose of 700?mg/kg, i.p., was most effective in suppressing KA-induced seizures, cognitive decline, and oxidative stress in the brain. These neuroprotective effects may be due to the antioxidant and anti-inflammatory effects of HAEEO.     

Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant

Rationale  

Orexins play a key role in the maintenance of alertness and are implicated in the modulation of diverse physiological processes, including cognitive function. Almorexant, a dual orexin receptor antagonist, transiently and reversibly blocks the action of orexin peptides at both OX₁ and OX₂ receptors and increases time spent in rapid eye movement (REM) and non-REM sleep.