Prolame ameliorates anxiety and spatial learning and memory impairment induced by ovariectomy in rats

N-(3-hydroxy-1, 3, 5 (10) estratrien-17beta-yl)-3-hydroxypropylamine (17β aminoestrogen, prolame) is a steroidal compound with weak estrogen-related trophic-proliferative effects in uterus. Contrasting with 17β-estradiol (E2) pro-coagulant effects, this compound has high anticoagulant and antiplatelet effects. It has been extensively demonstrated that E2 plays important roles in brain function. However, prolame's influence on central nervous system has not been documented. In this study, we evaluated the effects of prolame replacement in young ovariectomized rats on spatial learning and memory and anxiety, correlating pyramidal cell dendritic spine density changes and neuronal nitric oxide synthase (nNOS) expression in the hippocampus. Ovariectomized young rats were treated with prolame for 4 weeks. Three other groups were used as physiological, pathological, and pharmacological references as follow: gonadally intact cycling females, ovariectomized, and ovariectomized with 17β-estradiol treatment respectively, for the same time period. Experiment 1 investigated the behavioral effects of prolame on anxiety and spatial learning using elevated plus maze (EPM) and Morris water maze (MWM) paradigms respectively. Experiment 2 studied the dendritic spine density and neuronal nitric oxide synthase expression in the hippocampus of the 4 experimental groups. Similar to estradiol, prolame reversed the anxiogenic effects of ovariectomy, evaluated by EPM, and enhanced MWM performance to the level of gonadally intact subjects. Hippocampi from prolame-treated rats exhibited enhanced nNOS immunoreactivity and its relocation in dendritic compartments, as well as recovery of dendritic spine density loss in pyramidal neurons. Hence, prolame may provide an alternative option for ameliorating neurological symptoms caused by surgical menopause.     

Naloxone attenuates the conditioned place preference induced by wheel running in rats

Pairings, during which an episode of wheel running is followed by confinement in a distinctive place, produce conditioned place preference (CPP) in rats. This finding indicates that wheel running has a rewarding effect that outlasts the activity itself. In two similar experiments, we tested the hypothesis that this rewarding effect of wheel running is mediated by endogenous opioids. During a paired trial, the rats in the naloxone group were first allowed to wheel run for 2 h, then injected with naloxone (0.5 or 0.1 mg/kg in Experiments 1 and 2, respectively), and 10 min later placed in a distinctive chamber. During an unpaired trial, these rats were confined in an adjoining chamber without wheel running. Naloxone was injected before placement in both chambers, so that if naloxone-induced conditioned place aversion occurred, it would have counteracting effects on performance during the preference test. The rats in the saline group were similarly treated, except that saline was injected instead of naloxone. CPP occurred in the saline group, but not in the naloxone group. Thus, naloxone attenuated the CPP induced by wheel running. This finding supports the hypothesis that the rewarding effect of wheel running is mediated by endogenous opioids.     

MiR-181a influences the cognitive function of epileptic rats induced by pentylenetetrazol

Our previous study showed that the expression of miR-181a in memory impairment group of pentylenetetrazol (PTZ)-induced epileptic rats was up-regulated, but whether miR-181a influenced the cognitive function of PTZ-induced epileptic rats remains unknown. Therefore, we investigated the role of miR-181a in the cognitive function of PTZ-induced epileptic rats. A model of temporal lobe epilepsy (TLE) was induced via PTZ kindling in SD male rats. The epileptic rats were divided into Epilepsy group, Agomir-control group, miR-181a agomir group, 12 rats for each. 12 rats were used as sham group. We found that compared to the sham group, the expression of miR-181a in the Epilepsy group was increased. We also found that escape latency in the 5th day was prolonged and crossing times in the 6th day was reduced via Morris Water Maze test, which may indicate memory impairment. Furthermore, over-expression of miR-181a effectively reduced Bcl-2 protein level and increased apoptosis in hippocampus. Moreover, compared with Agomir-control group, the escape latency of miR-181a agomir group was obviously induced (P<0.05). Our findings suggest that miR-181a may play a role in impairing the cognitive function of PTZ-induced epileptic rats, and miR-181a could decrease the Bcl-2 protein and induce the apoptosis in the hippocampus that might be the way to impair cognitive function.     

Deficits in spatial memory performance induced by early undernutrition

Recent studies have shown that rats have a remarkable ability to keep track of their spatial location. Explanations stress the involvement of a form of short-term (working) memory in which the hippocampus appears to play a major role. The hippocampus appears to be vulnerable to early undernutrition and preliminary investigations indicate that Areas CA3 and CA4 suffer the most. Ninety-day-old rats, previously undernourished prenatally and throughout lactation, were tested in an 8- and, then, a 16-arm radial maze. Significant differences were observed between the experimental and control groups on both tests, especially in the 16-arm maze. Error distributions were also significantly different with experimental animals tending to perseverate in 1 area of the maze. Differences were also observed in the time taken to make the choices and in exploratory behavior. We conclude that early undernutrition affected the spatial learning ability of the animals and that this may be due to the distortions observed in the normal growth pattern of the hippocampus.     

Nimodipine improves the disruption of spatial cognition induced by cerebral ischemia

The direct neuroprotective effect of nimodipine, a central Ca antagonist, was investigated in in vitro experiments. Also, in in vivo experiments, the effects of nimodipine and amlodipine, a noncentral Ca antagonist, on rat cerebral ischemia models developing by different mechanisms were compared. In an in vitro ischemic model using acidotic and hypoglycemic rat cerebellar granule cells, nimodipine directly protects against brain neuronal cell damage. In in vivo models of single (one 10-min, four-vessel occlusion) and repeated rat cerebral ischemia (two 10-min, four-vessel occlusions; a 50-min interval), the impairment observed 24 h after the single ischemic procedure was likely to be prevented by nimodipine (0. 1-5mg/kg, i.p.). At 7 days after the repeated cerebral ischemia, the disruption of spatial cognition was significantly prevented by nimodipine (5 mg/kg, i.p.) but not amlodipine (5 mg/kg, i.p.), which was given after each ischemia. These results indicated that nimodipine may protect neuronal cells by a more persistent mode of action, that is, nimodipine may enter into the cell and control the intracellular Ca ion cascade by inhibiting excessive Ca(2)+ influx into the mitochondria.     

Naloxone pro-drug rescues morphine induced respiratory depression in Sprague-Dawley rats

Respiratory depression is the main obstacle for the safe administration of morphine for acute pain after injury. Due to this complication, new delivery methods are needed to insure that safe and effective doses of opioid analgesics are administered during emergencies. A depot formulation containing a naloxone pro-drug was designed to release the antidote when morphine causes dangerous hypoxic conditions in the blood. The aim of this work was to test the naloxone release in vivo in response to a severe overdose of morphine in the Sprague-Dawley rat model. Non-invasive two-chamber plethysmography was used to monitor and record respiration and to test the capability of the naloxone pro-drug to respond to and rescue morphine-induced respiratory depression in the animal. We show that the pro-drug formulation can both prevent and reverse severe morphine induced respiratory depression. The animal model demonstrates that co-administration of the naloxone pro-drug reliably antagonizes profound respiratory depressive effects of morphine.     

Mediodorsal thalamic stimulation is not protective against seizures induced by amygdaloid kindling in rats

Deep brain stimulation (DBS) is now emerging as a new option for treating intractable epilepsy. Cumulative studies suggest that the mediodorsal thalamic nucleus (MD) is involved in limbic seizure activity. This study aims to investigate whether DBS of the MD can protect against seizures induced by amygdaloid kindling. We studied the effect of low-frequency stimulation (LFS, 1 Hz) or high-frequency stimulation (HFS, 100 Hz) in the MD on amygdaloid kindling seizures. During the kindling acquisition, DBS in the MD was daily administered immediately after the kindling stimulus or before the kindling stimulus (preemptive DBS). The effects of both post-treatment of DBS and preemptive DBS in the MD on the expression of amygdaloid kindling seizures were evaluated. We found the DBS or preemptive DBS in the MD, either LFS or HFS, did not significantly change the rate of amygdaloid kindling. Similarly, DBS or preemptive DBS in the MD did not significantly change any parameters representing the expression of amygdaloid kindling. Our study suggests that DBS in the MD may have no significant effect on limbic seizures.     

Mechanisms of kindling induced by norbornan intoxication

Single injection of norbornan induced kindling by disordering postsynaptic GABAergic structures. Modulation of GABA_A receptor chlorine ionic channels is most crucial, while disturbances in postsynaptic low-affinity GABA_A receptors are less important for this phenomenon. It is unlikely that GABA_B, dopamine, and muscarinic neurotransmitter structures are involved into this process. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 6, pp. 653–656, June, 1998     

Acceleration of pentylenetetrazol seizure kindling associated with induction of sensitized visual responses evoked by strobe stimulation

Exposure of normal adult rats of a variety of species to trains of light flashes leads to acquisition of an enduring high amplitude visual cortical response [Uhlrich DJ, Manning KA, O'Laughlin ML, Lytton WW (2005) Photic-induced sensitization: acquisition of an augmenting spike-wave response in the adult rat through repeated strobe exposure. J Neurophysiol 94:3925–3937]. The photically-induced sensitized response exhibits epileptiform characteristics, including spike-wave morphology, tendency to generalize across the brain, and sensitivity to the anti-epileptic drug ethosuximide. These findings and anecdotal clinical reports raise the possibility that certain sensory stimulation could induce neural plastic changes that affect seizures in some individuals. We hypothesize that photic-induced sensitization can prime seizure-related neural circuitry, resulting in exacerbation of seizures. To test this we compared seizure kindling rates using the pentylenetetrazol (PTZ) model of epileptogenesis in sensitized and unsensitized adult Sprague–Dawley rats. Experimental group rats were sensitized by exposure to repetitive stroboscopic stimulation over 4–6 days until the sensitized photic response fully developed and response magnitude stabilized at its highest plateau. Rats then received a sub-convulsive injection of PTZ (24 mg/kg i.p.) every other day until they attained class 5 seizures. Control rats were not strobed or sensitized, but were otherwise treated identically. Chronic electrodes overlying the dura in occipital cortex recorded the primary visual response. Similar electrodes near the border of somatosensory and motor cortex (SM) were used to record spread of the sensitized response to a patently non-visual region. Rat behavior was monitored by direct observation and digital audio/video recording. All control rats and seven of 14 photically sensitized rats kindled seizures at rates consistent with those reported previously. However, the seven other photically sensitized rats displayed markedly accelerated seizure kindling. Rats with accelerated kindling showed greater spread of the sensitized visual response to somato-motor cortex and, when tested in a post hoc experiment, exhibited a higher likelihood of photo-triggered seizures. These results indicate that photic-induced sensitization in susceptible individuals can prime neural circuitry involved in the generation of PTZ-kindled seizures.     

Atorvastatin improves peritoneal sclerosis induced by hypertonic PD solution in rats

BACKGROUND: Peritoneal sclerosis is a complication of peritoneal dialysis and results in ultrafiltration failure. It is related to chronic peritoneal injury due to dialysis solution content and recurrent peritonitis. Statins have anti-inflammatory properties which may be of value in modulating responses to injury. We evaluated the capacity of atorvastatin to modify peritoneal alterations secondary to hypertonic glucose. METHODS: Thirty-two non-uremic rats were divided into three groups: group I (Sham) rats received no treatment (n=11), group II received hypertonic (3.86%, 10 ml/day) PD solution (n=10) and group III received hypertonic PD solution (10 ml/day) plus 80 mg/L atorvastatin in drinking water (n=11). After four weeks, a one-hour peritoneal equilibration test (PET) was performed with 3.86% PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D 1 /D 0 glucose), ultrafiltration volume (UF), dialysate protein, TGF-beta 1 and VEGF levels were determined. RESULTS: Administration of atorvastatin resulted in preserved UF (4.9+/-0.8 vs 7.5+/-0.6 mL, p <0.01), protein loss (2.2+/-0.2 vs 2.1+/-0.1 g/L, p >0.05), and peritoneal thickness (53+/-3 vs 26+/-4 microm, p <0.01). D 1 /D 0 glucose was significantly reduced in the dextrose group (0.70+/-0.02 vs 0.56+/-0.04, p <0.01). Both higher levels of TGF-ss 1 (206+/-40 vs 474+/-120 pg/mL, p<0.05), and VEGF in dialysate effluent (4+/-0.4 vs 7.9+/-3 pg/mL, p>0.05), was determined in the dextrose group. CONCLUSION: Exposure to hypertonic glucose solution resulted in alterations in peritoneal transport manifested by a rapid dissipation of the glucose gradient and resultant impaired UF response. Administration of atorvastatin led to prevention of these alterations. We suggest that the anti-inflammatory properties of statins are useful in providing protection of the peritoneal membrane from the effects of hypertonic glucose.     

Early antibiotic administration prevents cognitive impairment induced by meningitis in rats

Neurological deficit and alterations in the hippocampus still frequently occur following bacterial meningitis in children, despite the antibiotic treatment. We investigated the long-term outcomes using early versus late antibiotic therapy in experimental pneumococcal meningitis. To this aim, male Wistar rats underwent a basilar cistern tap receiving either sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension. Antibiotics were started 8 or 16 h after infection and the animals were followed for 10 days to the determination of long-term cognitive outcomes. The animals were submitted to the habituation of an open-field as an index of long-term cognitive function. Early antibiotic administration (8 h after inoculation) when compared to late antibiotic administration (16 h after inoculation) prevented cognitive impairment induced by pneumococcal meningitis in Wistar rats. The findings from this study suggest that early antibiotic administration is an effective strategy to prevent long-term cognitive impairment in a meningitis animal model.     

Long-lasting potentiation effects induced in rats by kindling with an inverse agonist of the benzodiazepine receptor

The present work analyzed the changes in evoked field potentials of freely moving rats after kindling induced by a convulsant inverse agonist of the GABA(A)-benzodiazepine receptor complex, methyl beta-carboline-3-carboxylate (beta-CCM). Two doses of beta-CCM (2 mg/kg and 4 mg/kg) were used. In kindled and control animals, a stimulating electrode was implanted in the perforant pathway and a recording electrode in the dentate gyrus. Results showed that, after an acutely injected dose of 20 mg/kg pentylenetetrazol (PTZ), all kindled animals showed a decrease in population spike amplitude after 20 min. After 60 min, only fully kindled rats showed a long-lasting potentiation, also visible up to 24 h later, as compared to controls or nonkindled animals. Changes in glutamate and GABA receptor binding measured in previous experiments may explain this potentiation effect observed in fully kindled rats.     

Unilateral low-frequency stimulation of central piriform cortex delays seizure development induced by amygdaloid kindling in rats

Low-frequency stimulation of the kindling site interferes with the course of kindling epileptogenesis. The present study examined the effect of unilateral low-frequency stimulation of the central piriform cortex on seizure development induced by amygdaloid kindling in rats. The ipsilateral or contralateral central piriform cortex received low-frequency stimulation (15 min train of 0.1 ms pulses at 1 Hz and 50-150 muA) immediately after termination of once daily kindling stimulation (2 s train of 1 ms pulses at 60 Hz and 150-300 microA) in the right amygdala for 30 days. Low-frequency stimulation of either the ipsilateral or contralateral central piriform cortex significantly suppressed the progression of seizure stages and reduced afterdischarge duration throughout the course of amygdaloid kindling. The marked suppression induced by low-frequency stimulation of the central piriform cortex on either side was predominantly due to the significant retardation of progression from stage 0 to stage 1 and stage 3 to stage 4 seizures. In addition, the suppressive effect of low-frequency stimulation did not disappear when the stimulation was stopped; it could persist for at least 10 days. These findings indicate that brain areas other than the kindling focus, such as the central piriform cortex on both sides, can also be used as reasonable targets for low-frequency stimulation to retard seizure development induced by amygdaloid kindling. Secondly, like the ipsilateral central piriform cortex, the contralateral central piriform cortex may also participate in the progression and secondary generalization of focal seizures. The study suggests that unilateral low-frequency stimulation of the central piriform cortex may have a significant antiepileptogenic effect, and may be helpful for exploring effective and long-lasting therapies for human temporal lobe epilepsy.     

Pattern of NADPH-diaphorase active neurons in rat forebrain is unchanged after pentylenetetrazol kindling.

The activity of NADPH-diaphorase in rat telencephalic structures has been revealed by use of a histochemical method. Multiple neurons belonging to different nuclei were found to contain the enzyme. Furthermore, diaphorase reactive nerve fibres and terminal fields were observed to be widely distributed throughout rat brain. Chemical kindling induced by pentylenetetrazol (PTZ) did not effect the regional distribution and cellular localization of the enzyme in the rat CNS.     

Amygdala kindling increased fear-response, but did not impair spatial memory in rats.

The behavioral effects of amygdala kindling, a model of experimental epilepsy in rats, are reported. The animals were stimulated twice a day until stage 5 (generalized clonic) seizures were obtained three times. Two weeks later the performance of the amygdala-kindled and sham-operated rats was tested in the open-field test, on the elevated plus maze, elevated bridges, and in the Morris water maze. The results show that amygdala kindling decreased exploratory and other motor activity in the open-field test, had anxiogenic effects on the elevated plus-maze, decreased boldness on the elevated bridges, but had a negligible affect in the spatial memory task. These results suggest that amygdala kindling affects the normal fear reaction of rats, a response that is known to be mediated through the amygdaloid pathways.     

Scopolamine impairs spatial maze performance in rats

Male Wistar rats given repeated daily injections of scopolamine (0.3 mg/kg), or isotonic saline, over a 15 day acquisition period were trained in an 8-arm radial maze using a confinement procedure in which the animal was detained in the centre of the maze for 10 sec between each arm choice. Confinement was used to reduce the likelihood that animals would resort to non-spatial strategies to solve the maze. All scopolamine treated animals failed to learn over the 15 day period, since their performance never exceeded that of saline treated animals early in learning. On two days when treatments were reversed, the animals which had previously received scopolamine improved performance significantly, and those which had been given saline were impaired under scopolamine treatment.     

NSC23766改善大鼠脑缺血后认知功能缺陷

目的:探讨Rac1在大鼠海马CA1区缺血性神经元损伤中的作用.方法:健康成年雄性SD大鼠制作四动脉闭塞全脑缺血模型,实验动物随机分为Sham、缺血再灌组(ischemia/reperfusion,I/R)、溶剂对照(Vehicle)组(I/R+生理盐水)、NSC23766组(I/R+NSC23766).采用激光共聚焦显微镜技术观察海马CA1区生存神经元.利用Morris水迷宫观察脑缺血再灌注后大鼠的空间学习记忆功能的变化情况.结果:与缺血再灌注组相比,Rac1抑制剂NSC23766组海马CA1区神经元生存数量增加;大鼠缺血后的空间学习记忆缺陷明显得到改善.结论:Rac1的激活可能是导致大鼠缺血再灌注后神经元损伤的重要因素,其抑制剂NSC23766可有效减轻这种损伤,为临床治疗缺血性脑中风提供理论依据.     

Effects of ionotropic glutamate receptor channel blockers on the development of pentylenetetrazol kindling in mice

Experiments on mice were performed to study the ability of monocationic and dicationic adamantane and phenylcyclohexyl derivatives to prevent the development of kindling induced by i.p. administration of pentylenetetrazol (Corasol, 35 mg/kg). The monocationic phenylcyclohexyl derivative IEM-1921 effectively slowed the development of kindling, this being seen over a wide range of doses (0.0001–0.1 μmol/kg). A monocationic adamantane derivative (memantine), also a selective non-competitive blocker of NMDA receptors, produced a similar effect at doses 100 times higher. The anticonvulsive activity of the dicationic phenylcyclohexyl derivative IEM-1925, which could block both types of glutamate receptors, differed from the activity of the monocationic derivative by having a more complex dose-response relationship. Thus, the development of kindling was suppressed by essentially the same doses as needed for the monocation IEM-1921 (0.001 μmol/kg). However, on reducing the dose by a factor of 10 (0.0001 μmol/kg), IEM-1925 facilitated the development of kindling. This difference in the prophylactic activities of selective NMDA receptor blockers and substances able to block both NMDA and AMPA receptors provides evidence that the mechanism of kindling involves both types of ionotropic glutamate receptor and the effects of compounds depend not only on the ratio of the contributions of these receptors, but also on the kinetic characteristics of the blocking action. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 11, pp. 1241–1251, November, 2005.     

Delay improves performance on a haptic spatial matching task

Systematic deviations occur when blindfolded subjects set a test bar parallel to a reference bar in the horizontal plane using haptic information (Kappers and Koenderink 1999, Perception 28:781–795; Kappers 1999, Perception 28:1001–1012). These deviations are assumed to reflect the use of a combination of a biasing egocentric reference frame and an allocentric, more cognitive one (Kappers 2002, Acta Psychol 109:25–40). In two experiments, we have examined the effect of delay between the perception of a reference bar and the parallel setting of a test bar. In both experiments a 10-s delay improved performance. The improvement increased with a larger horizontal (left–right) distance between the bars. This improvement was interpreted as a shift from the egocentric towards the allocentric reference frame during the delay period. Electronic Publication     

Effects of epigallocatechin-3-gallate on pentylenetetrazole-induced kindling, cognitive impairment and oxidative stress in rats

Cognitive dysfunction is commonly observed in epileptic patients. It has been shown that not only epilepsy but also antiepileptic drugs could induce cognitive impairment. Thus, there is an urgent need for drugs that can suppress seizures without causing cognitive deficit. Recent studies have shown that oxidative stress is involved in the pathophysiology of epilepsy, and many antioxidants have an antiepileptic property. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The purpose of this study was to assess the effect of EGCG against seizures, seizure-induced oxidative stress and cognitive impairment in pentylenetetrazole-induced kindling. Male Sprague-Dawley rats were injected intraperitoneally with a dose of 35 mg/kg of pentylenetetrazole (PTZ) once every alternate day for 13 injections. EGCG was administered daily in two doses (25mg/kg and 50mg/kg) intraperitoneally along with alternate-day PTZ. Morris water maze test was carried out 24h after the last injection of PTZ, and the oxidative stress parameters (malondialdehyde and glutathione) were assessed after the completion of the behavioral test. The results showed that EGCG dose-dependently suppressed the progression of kindling. EGCG also ameliorated the cognitive impairment and oxidative stress induced by PTZ kindling. These observations suggest that EGCG may be a potential agent for the treatment of epilepsy as well as a preventive agent against cognitive impairment induced by seizure.