MK-801 is neuroprotective in gerbils when administered during the post-ischaemic period

The neuroprotective effects of the non-competitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) have been evaluated in the gerbil hippocampus when the drug was administered i.p. at various times during and after a 5 min period of transient forebrain ischaemia, induced by bilateral common carotid artery occlusion. A single dose of 1, 3 or 10 mg/kg of MK-801 gave significant protection of hippocampal CA1 and CA2 pyramidal neurons when administered during the occlusion and up to 24 h following the period of ischaemia. A dose of 0.3 mg/kg was effective when administered during the occlusion period but gave no protection at 30 min or 2 h post-ischaemia. Experiments in which MK-801 was administered in repeated doses indicated that significant protection was achieved with 1 mg/kg of MK-801 repeated post-ischaemically and with 1 mg/kg MK-801 supplemented with repeated doses of 0.3 mg/kg of MK-801. However 0.3 mg/kg of MK-801 followed by repeated doses of 0.03 mg/kg administered post-ischaemically was not neuroprotective. These results indicate that MK-801 can protect hippocampal neurons from ischaemia-induced neuronal degeneration when it is administered up to 24 h after the insult. These data provide further evidence that therapeutic intervention in the post-ischaemic period can successfully prevent neurodegenerative events, and that the delayed degeneration of hippocampal neurons following an ischaemic insult occurs by an N-methyl-D-aspartate receptor-mediated process.     

Neuronal damage and MAP2 changes induced by the glutamate transport inhibitor dihydrokainate and by kainate in rat hippocampus in vivo

 Neurotoxicity mediated by glutamate is thought to play a role in neurodegenerative disorders, and alterations in cytoskeletal proteins are possibly involved in the mechanisms of neuronal death occurring in Alzheimer’s disease. In the present work we studied the neurotoxic effects of the intrahippocampal injections of the glutamate transport inhibitor dihydrokainate as compared to those of kainate, as well as the concomitant changes in the microtubule-associated protein MAP2. Neuronal alterations were assessed at 3, 12, 24, and 48 h by Nissl staining and immunocytochemistry of MAP2. At 3 h, both compounds induced neuronal damage that was correlated with loss of dendritic MAP2 immunoreactivity. Neuronal damage was more evident at 12 h and 24 h after drug injection, and at these times an accumulation of MAP2 in the somata of pyramidal neurons was observed. The effects of dihydrokainate were restricted to the CA1 region and totally prevented by the N-methyl-d-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), but not by the non-NMDA receptor antagonist 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline (NBQX). In contrast, kainate-induced alterations included CA1, CA3, and CA4 subfields, and the changes in CA1 were prevented by NBQX, while MK-801 was ineffective. These results suggest that early MAP2 disruption may be a marker of the excitotoxicity due to activation of different glutamate receptors located in discrete hippocampal regions. Received: 2 December 1996 / Accepted: 7 April 1997     

Influence of dizocilpine (MK-801) on neurotoxic effect of dexamethasone: behavioral and histological studies

Elevated levels of endogenous glucocorticoids (GCs) or prolonged treatment with high doses of dexamethasone (DEX) or other GCs preparations are frequently associated with psychosis as well as cognitive deficits, such as the impairment of memory and learning. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids in the extracellular space of hippocampus. The antagonism of glutamate receptors may potentially improve safety profile of therapy with GCs. The purpose of the present study was to investigate the effect of dizocilpine maleate (MK-801), non-competitive NMDA glutamate receptor antagonist, on neurotoxic effect of the prolonged treatment with the high dose of DEX. The results showed that DEX (120 mg/kg/day for 7 days) impaired the long-term memory and the motor coordination, reduced the body weight and induced the lethality of mice. The morphological and ultrastructural study have confirmed damage to hippocampal neurons especially in the CA3 region after the prolonged treatment with DEX alone. Damaged pyramidal neurons showed robust changes in the shape of the nucleus and cytoplasm condensation. MK-801 alone (at non-toxic dose of 0.3 mg/kg/day), changed neither the behavior of mice nor morphology of the hippocampal neurons. However, it did not prevent the neurotoxic effects of DEX. On the contrary, it intensified DEX-induced neurotoxicity.     

离子型谷氨酸受体拮抗剂MK-801浓度与全脑缺血再灌注大鼠海马内源性神经干细胞的增殖**

背景：脑缺血再灌注后,过度释放的兴奋性氨基酸可通过N-甲基-D-天冬氨酸(NMDA)受体激活内源性神经干细胞,促使其增殖、分化,修复神经细胞,但同时也导致细胞内钙离子超载,引起神经细胞的损伤。 目的：观察NMDA受体拮抗剂MK-801浓度对脑缺血再灌注大鼠海马内源性神经干细胞增殖的影响。 方法：SD大鼠随机分为正常对照组、手术对照组及MK-801 0.2,0.4,0.6,0.8,1.0,1.2 mg/kg组。除正常对照组外,大鼠首先进行侧脑室插管,3 d后进行4条血管阻断方法制备大鼠全脑缺血再灌注模型。在模型制作前30 min按照不同浓度侧脑室注射MK-801。正常对照组和手术对照组侧脑室注射同剂量的生理盐水。免疫组织化学、RT-PCR技术检测各组脑海马nestin阳性细胞及其mRNA表达。 结果与结论：MK-801浓度在0.8 mg/kg以下时,用药组大鼠脑海马nestin mRNA及蛋白的表达与手术对照组差异无显著性意义(P > 0.05),呈现高表达;当MK-801浓度达到0.8 mg/kg时,与手术对照组相比,用药组大鼠脑海马nestin基因及蛋白的表达明显下降(P < 0.05),并随浓度的增高呈递减趋势。提示MK-801在浓度为0.6 mg/kg时,即可抑制钙超载保护神经元,又有良好的刺激神经干细胞增殖作用。 关键词：离子型谷氨酸受体拮抗剂;脑缺血;再灌注;神经干细胞;MK-801 doi:10.3969/j.issn.1673-8225.2012.06.012     

Delayed apoptotic pyramidal cell death in CA4 and CA1 hippocampal subfields after a single intraseptal injection of kainate

We have performed a detailed time-course analysis of cell death in the hippocampal formation, basal forebrain and amygdala following a single intraseptal injection of kainate in adult rats. Acetylcholinesterase histochemistry revealed a profound loss of staining in the medial septum but not in the diagonal band, and cholinergic fiber density was highly reduced in the hippocampus and amygdala at 10 days postinjection. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphatebiotin nick end labeling (TUNEL) histochemistry was performed for precise location of apoptotic cells. Both the medial septum and amygdala exhibited numerous TUNEL-positive nuclei after the intraseptal injection of kainate, while the lateral septum exhibited a lower but significant incidence in terms of apoptotic cells. In the medial septum, the presence of apoptotic cells was at a location displaying acetylcholinesterase staining. TUNEL histochemistry revealed a time-dependent sequential apoptotic cell death in hippocampal pyramidal cells. During the first two days postinjection, apoptosis in the hippocampus was only evident in the CA3 region. At five days postinjection, the entire CA4 region became apoptotic. At 10 days postinjection, the whole extent of the CA1 pyramidal cell layer exhibited numerous TUNEL-positive nuclei. The time-course of kainate-induced apoptosis in Ammons's horn correlated with the disappearance of hippocampal pyramidal neurons as detected by Nissl staining, which is suggestive of a prominent apoptotic death for these cells. The temporal delayed distant damage to CA4 and CA1 hippocampal subfields after a single intraseptal kainate injection is not seen in other models employing kainate and may be a valuable tool for exploring the cellular mechanisms leading to cell death in conditions of status epilepticus.     

Systemic administration of MK-801 protects against N-methyl-D-aspartate- and quisqualate-mediated neurotoxicity in perinatal rats

MK-801, a non-competitive antagonist of N-methyl-D-aspartate-type glutamate receptors, was tested for its ability to antagonize excitotoxic actions of N-methyl-D-aspartate or quisqualic acid injected into the brains of seven-day-old rats. Stereotaxic injection of N-methyl-D-aspartate (25 nmol/0.5 microliters) or quisqualic acid (100 nmol/1.0 microliter) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies. N-Methyl-D-aspartate produced severe, confluent neuronal destruction while quisqualic acid typically caused more selective neuronal necrosis. Intraperitoneal administration of MK-801 (0.1-1.0 mg/kg) 30 min before N-methyl-D-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. A 1 mg/kg dose of MK-801 given as pre-treatment completely protected the infant brain. The same dose of MK-801 was also completely protective when administered 30 or 40 min after N-methyl-D-aspartate and afforded partial protection when given 2 h later. MK-801 pre-treatment also prevented the electrically confirmed behavioral seizures induced by N-methyl-D-aspartate. The drug significantly reduced striatal but not hippocampal or neocortical injury when given as two doses (1 mg/kg) 30 min prior to and immediately following quisqualic acid injection. The data indicate that systemic administration of MK-801 can prevent N-methyl-D-aspartate-induced neuronal injury in perinatal rat brain even when administered after the initial insult. MK-801 also partially antagonized quisqualic acid-mediated neurotoxicity, suggesting that quisqualic acid-induced toxicity is, in part, mediated through N-methyl-D-aspartate receptor activation. The sensitivity of the developing brain to the toxicity of N-methyl-D-aspartate provides a sensitive and reproducible in vivo model for exploring these issues and for screening prospective neuroprotective drugs that act at the N-methyl-D-aspartate receptor-channel complex.     

MK-801对新生鼠脑外伤性神经变性的超微结构的影响

目的:研究非竞争性N-甲基-D-天门冬氨酸受体拮抗剂MK-801对新生鼠创伤性颅脑损伤(TBI)后同侧顶叶皮质和海马神经元超微结构的影响.方法:新生7 d SD大鼠,被随机分成正常对照组和实验组(实验组给予MK-801 1 mg/kg,并且细分为创伤前30 min给药、创伤即刻给药和创伤后30 min给药3个亚组).造模24 h取材,透射电镜下观察神经细胞超微结构的变化.结果:创伤后30 min给药的神经细胞出现胞质和核染色质的浓缩深染,胞质内充满大小不等的空泡;创伤即刻组的神经细胞胞质内线粒体有肿胀,但胞核的变化不明显.结论:适时和适量运用MK-180能延迟神经细胞核染色质和粒线体的变性损伤,使之停留在损伤早期,为临床联合其他药物治疗赢得时间.     

Neuroprotective effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid: evaluation by magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy

Magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy were used to evaluate the therapeutic effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid. Systemic administration of 3-nitropropionic acid (15 mg/kg per day) to two-month-old Sprague-Dawley rats (n = 10 for each group) for five consecutive days induced selective striatal and hippocampal lesions and specific behavioral change. Pretreatment with lamotrigine (10 mg/kg or 20 mg/kg per day) or MK-801 (2 mg/kg per day) attenuated the lesions and behavioral change. There were no significant differences in T2 values of the striatum and hippocampus among rats pretreated with MK-801, lamotrigine (20 mg/kg) and sham controls. Significant elevations of succinate/creatine and lactate/creatine ratios and decreases of N-acetylaspartate/creatine and choline/creatine ratios were observed after 3-nitropropionic acid injections (P < 0.001). The changes were nearly prevented after pretreatment with lamotrigine (20 mg/kg). However, the N-acetylaspartate/creatine in rats pretreated with lamotrigine (10 mg/kg) (P < 0.01) and MK-801 (P < 0.05) still showed significant reduction as compared with sham controls. Thus we conclude that both lamotrigine and MK-801 are effective in attenuation of brain lesions induced by 3-nitropropionic acid. A higher dose of lamotrigine provides a better neuroprotective effect than MK-801. With a better therapeutic effect and fewer side effects, lamotrigine is more promising for potential clinical application.     

Participation of NMDA-glutamatergic receptors in hippocampal neuronal damage caused by adult-onset hypothyroidism

We analyzed the participation of N-methyl-d-aspartate (NMDA) receptors in the neuronal damage caused by adult-onset hypothyroidism. Wistar rats were randomly assigned into four groups. The euthyroid group received tap water. The hypothyroid group received methimazole (60 mg/kg) in their drinking water to induce hypothyroidism. Two more groups of rats received the antithyroid treatment and were injected daily with the NMDA antagonist ketamine (15 mg/kg, sc) or MK-801 (0.5 mg/kg, ip). Treatments were administered during 4 weeks. At the end of the respective treatments rats were deeply anaesthetized and perfused intracardially with 0.9% NaCl followed by 4% paraformaldehyde. The brains were removed from the skull, and coronal brain sections (7 μm thick) were obtained. Neurons were counted in the CA1, CA2, CA3, and CA4 hippocampal regions differentiating between normal and atrophic cells by an experimenter blind to the treatment. The percentage of neuronal damage found in the MMI group was significantly greater in the hippocampal regions compared to the euthyroid group. In contrast, both NMDA antagonists were able to prevent the neuronal damage secondary to hypothyroidism in all hippocampal regions. Our results suggest that the neuronal damage caused in the hippocampus of adult-onset hypothyroid rats requires activation of NMDA channels.     

NMDA receptor antagonism impairs reversal learning in developing rats

Four experiments examined the effect of dizocilpine maleate (MK-801), a noncompetitive N-methyl-Daspartate (NMDA) receptor antagonist, on reversal learning during development. On postnatal days (PND) 21, 26, or 30, rats were trained on spatial discrimination and reversal in a T-maze. When MK-801 was administered (intraperitoneally) before both acquisition and reversal, 0.18 mg/kg generally impaired performance, whereas doses of 0.06 mg/kg and 0.10 mg/kg, but not 0.03 mg/kg, selectively impaired reversal learning (Experiments 1 and 3). The selective effect on reversal was not a result of sensitization to the second dose of MK-801 (Experiment 2) and was observed when the drug was administered only during reversal in an experiment addressing state-dependent learning (Experiment 4). Spatial reversal learning is more sensitive to NMDA-receptor antagonism than is acquisition. No age differences in sensitivity to MK-801 were found between PND 21 and 30.     

VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo.

N-methyl-D-aspartate receptor/channel (NMDAR) and voltage-dependent calcium channel (VDCC) antagonists applied independently reduce the magnitude of long-term potentiation (LTP) in area CA1 of the hippocampal slice preparation. When used in combination, the antagonists completely block the induction of LTP. In urethan-anesthetized rats we examined the effect of the NMDAR blocker MK-801 (0.1 mg/kg) and the VDCC blocker Verapamil (10 mg/kg) on LTP induction in area CA1. Extracellular recordings were obtained from stratum radiatum following stimulation of Schaffer collaterals. LTP was induced by a 200-Hz/100-ms tetanus repeated 10 times (2 s isi). Tetanus was given in the presence of intraperitoneal saline, MK-801, Verapamil, or both Verapamil and MK-801. When given separately, Verapamil and MK-801 both significantly reduced the magnitude of LTP as compared with control animals. When given together, the drugs blocked the induction of LTP completely. We conclude that like LTP in vitro, VDCCs and NMDAR underlie two forms of LTP in vivo.     

Short- and long-term changes in CA1 network excitability after kainate treatment in rats

Neuron loss, axon sprouting, and the formation of new synaptic circuits have been hypothesized to contribute to seizures in temporal lobe epilepsy (TLE). Using the kainate-treated rat, we examined how alterations in the density of CA1 pyramidal cells and interneurons, and subsequent sprouting of CA1 pyramidal cell axons, were temporally associated with functional changes in the network properties of the CA1 area. Control rats were compared with animals during the first week after kainate treatment versus several weeks after treatment. The density of CA1 pyramidal cells and putative inhibitory neurons in stratum oriens was reduced within 8 days after kainate treatment. Axon branching of CA1 pyramidal cells was similar between controls and animals examined in the first week after kainate treatment but was increased several weeks after kainate treatment. Stimulation of afferent fibers in brain slices containing the isolated CA1 region produced graded responses in slices from controls and kainate-treated rats tested <8 days after treatment. In contrast, synchronous all-or-none bursts of spikes at low stimulus intensity (i.e., "network bursts") were only observed in the CA1 several weeks after kainate treatment. In the presence of bicuculline, the duration of evoked bursts was significantly longer in CA1 pyramidal cells weeks after kainate treatment than from controls or those examined in the first week posttreatment. Spontaneous network bursts were also observed in the isolated CA1 several weeks after kainate treatment in bicuculline-treated slices. The data suggest that the early loss of neurons directly associated with kainate-induced status epilepticus is followed by increased axon sprouting and new recurrent excitatory circuits in CA1 pyramidal cells. These changes characterize the transition from the initial acute effects of the kainate-induced insult to the eventual development of all-or-none epileptiform discharges in the CA1 area.     

Kainate-induced seizures, oxidative stress and neuronal loss in aging rats

Aging is a significant risk factor for developing epilepsy. The mechanisms underlying age-related increase in seizure susceptibility and resultant injury remain unknown. Oxidative stress is an important mechanism that contributes to diverse age-related disorders. Whether age-related increased seizure susceptibility is accompanied by increased oxidative stress remains unknown. The goal of this study was to determine if aging per se increases the susceptibility of rats to kainate-induced behavioral seizures and oxidative stress. Adult (3-4 month-old) and aging (18-19 month-old) Sprague-Dawley rats were administered a single low dose of kainate (5 mg/kg, s.c.) or saline. Behavioral seizures were monitored in all four groups for a period for a period of approximately 6 h. Oxidative stress (8-hydroxy-2'deoxyguanosine/2-deoxyguanosine; 8OHdG/2dG) was assessed 24 h following kainate injection. Stereological assessment of cell counts was performed in hippocampal tissue 7 days following kainate injection. In adult rats, administration of the low dose of kainate did not produce significant behavioral seizures, oxidative stress or cell loss. However, aging rats exhibited intense behavioral seizures consistent with status epilepticus following the low dose of kainate. In aging rats, kainate produced a significant increase in oxidative DNA damage (8OHdG/2dG) and neuronal loss in cornu ammonis regions 3 and 1 (CA3 and CA1), but not dentate gyrus compared with both age-matched controls and adult kainate-treated rats. These data suggest that the process of aging per se increases kainate-induced seizure susceptibility, oxidative stress and hippocampal pyramidal cell loss.     

Protection of CA1 pyramidal cell function by MK-801 following ischaemia in the gerbil

Electrophysiological recordings were made from hippocampal slices of gerbils which had undergone a 5 min period of bilateral carotid occlusion. Normal CA1 population spikes, field potentials and synaptic responses were obtained from slices of gerbils pretreated with the N-methyl-D-aspartate antagonist, MK-801 (10 mg/kg, i.p., 1 h before the occlusion). In contrast, no CA1 population spike could be obtained from slices of untreated gerbils, although field potentials and population spikes were obtained from the dentate granule cell region of these slices in response to perforant path stimulation. These studies indicate that the CA1 pyramidal cells identified histologically as protected by MK-801 from selective neuronal degeneration produced by a 5 min period of global ischaemia, are also functionally protected and retain their normal synaptic responsiveness.     

N-methyl-D-aspartate-induced excitotoxicity in adult rat retina is antagonized by single systemic injection of MK-801

Intravitreal injection of N-methyl-D-aspartate (NMDA) produced a substantial damage to the adult rat retina that was largely restricted to inner retinal layers, including the ganglion cell layer (GCL), inner nuclear layer (INL), inner, and outer plexiform layers. This retinal damage was significantly reduced by a systemic injection of a low dose of MK-801 (0.5 mg/kg), a potent NMDA-receptor antagonist. This neuroprotection was dose dependent and was most effective when the antagonist was given 1 h before NMDA insult. An intraperitoneal injection of 0.5 mg/kg MK-801 provided a virtually complete protection to the retina to the NMDA-induced toxicity, as indicated quantitatively by the number of DiI-filled retinal ganglion cells, the number of cells in the GCL and INL that undergo DNA fragmentation, and the edematous changes in retinal thickness. A post-lesion administration of MK-801 was still able to provide an effective neuroprotective effect to the retina, but this protection was lost when MK-801 was given 4 h after NMDA exposure. The current results indicate a therapeutic potential of systemic application of MK-801 in protecting the adult rat retina from neurologic disorders related to excessive activation of NMDA receptors.     

Increased excitatory synaptic activity and local connectivity of hippocampal CA1 pyramidal cells in rats with kainate-induced epilepsy

Formation of local excitatory circuits may contribute to epileptogenesis. We tested the hypothesis that epileptogenesis is associated with increased recurrent excitation in the hippocampal CA1 area of rats with kainate-induced epilepsy. Whole cell recordings were obtained during focal flash photolysis of caged glutamate, which served as a focal excitant to activate local pyramidal cells and to study possible connections between neurons. Kainate-treated rats with spontaneous seizures were studied months after status epilepticus and were compared with saline-injected control rats. Experiments were done in isolated CA1 minislices and in bicuculline to block GABA(A) receptors. Spontaneous excitatory postsynaptic currents (sEPSCs) were present in 42% of the CA1 pyramidal cells from controls and 62% from kainate-treated rats. The frequency of sEPSCs in the kainate group was significantly higher than that in the control group, but mean amplitude was not different. Flash photolysis of caged glutamate on the somatodendritic area of CA1 pyramidal neurons caused a burst of action potentials. Local excitatory connections between CA1 pyramidal cells were found in 4 of 48 neurons (8%) in slices from control animals, but in significantly more neurons (12 of 37; 32%) from rats with kainate-induced epilepsy exhibited interconnections (P < 0.001). Photoactivation of glutamate on recorded CA1 pyramidal cells in the kainate group sometimes caused afterdischarges, but not in controls. The kainate-treated rats with pyramidal cells that responded to photostimulaltion with repetitive EPSCs appeared to have experienced more severe seizures. These data provide new electrophysiological evidence for the formation of recurrent excitatory circuits in the CA1 area of rats with kainate-induced epilepsy.     

The nicotinic agonist RJR-2403 compensates the impairment of eyeblink conditioning produced by the noncompetitive NMDA-receptor antagonist MK-801

The classical conditioning of eyelid responses using trace paradigms is a hippocampal-related model of associative learning, involving the activation of N-methyl-D-aspartate (NMDA) receptors. We have evaluated here the effects of NMDA-receptor blockage with the selective noncompetitive antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine, MK-801). Mice were implanted with stimulating electrodes on the supraorbitary nerve and with recording electrodes in the ipsilateral orbicularis oculi muscle. Animals were conditioned with a trace shock-SHOCK paradigm. MK-801-injected animals (0.02 mg/kg) seemed unable to acquire this type of associative learning task, but the latency and amplitude of their unconditioned eyelid responses was not affected by drug administration. The administration of the nicotinic agonist (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403; 2 mg/kg) was able to restore completely the acquisition of the conditioned response when administered both before and after MK-801. In vitro recordings of field excitatory postsynaptic potentials (fEPSPs) evoked in the hippocampal CA1 area by the electrical stimulation of the Schaffer collateral pathway indicates that RJR-2403 application to the bath enhance the release of glutamate by a presynaptic mechanism. These findings reveal that nicotinic acetylcholine receptors enhance glutamatergic transmission in hippocampal circuits involved in the acquisition of associative learning.     

粉防己碱对戊四唑致(癎)大鼠皮层电图和海马超微结构的影响

目的:探讨钙拮抗剂粉防己碱(tetradrine,Tet)对戊四唑(Pentylentetrazol,PTZ)诱导的大鼠癫(癎)模型的作用.方法:健康SD大鼠24只,随机分为4组,对照组和Tet 3个剂量组(15 mg/kg,30 mg/kg,60 mg/kg)各6只.观察大鼠腹腔注射PTZ前后癫(癎)发作的情况,按Racine分级标准分级,同时记录皮层电图(ECoG),观察PTZ注射后到出现(癎)样放电的潜伏期及1 h内(癎)样放电累加的持续时间.电镜观察海马神经元超微结构的改变.结果:对照组给PTZ后均出现癫(癎)发作,程度均为5级,Tet组发作程度明显减轻.ECoG上出现(癎)样放电的潜伏期延长,(癎)样放电在1 h中的持续时间缩短.同时,Tet也能明显减轻PTZ致(癎)大鼠海马CA1区锥体细胞线粒体的损伤程度.结论:Tet对PTZ诱导的癫(癎)大鼠的发作有明显的对抗作用,对海马锥体神经元的拟伤具有保护作用.