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.     

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.     

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.     

Kainate-induced functional deficits are not blocked by MK-801

Male, Fischer-344 rats were pretreated with MK-801 (0.1, 1.0 or 10.0 mg/kg, i.p.) prior to bilateral injection of kainate (0.33 micrograms/site) into the dorsal and ventral hippocampus. Kainate impaired the acquisition of a water maze acquisition task 4 weeks after surgery, an effect not attenuated by pretreatment with MK-801. However, higher doses (1.0 and 10.0 mg/kg) of MK-801 reduced the amount of kainate-induced granule cell and to some extent CA1 pyramidal cell damage in the hippocampus. Kainate-induced CA3/CA4 damage was not affected by MK-801 pretreatment. MK-801 (10 mg/kg) also reduced the amount of thalamic damage produced by kainate. These data support the conclusion that intrahippocampal kainate-induced destruction of CA3/CA4 pyramidal cells is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors and that kainate-induced loss of these cells is associated with the neurobehavioral effects of intrahippocampally administered kainate.     

低剂量木黄酮降低缺血后神经元损伤并改善学习记忆功能

目的探讨染料木黄酮(GEN)对全脑缺血(GCI)大鼠海马CA1区神经元的神经保护作用及其可能的机制。方法建立大鼠4动脉结扎全脑缺血模型,实验动物随机分为假手术组(sham)、缺血再灌注组(I/R)、GEN处理组、ICI 182,780组和溶剂对照组。采用Fluoro-Jade B和神经元特异性核蛋白(NeuN)染色观察海马CA1区神经元存活情况,TUNEL技术观察海马CA1区神经元的凋亡。Morris水迷宫观察大鼠的空间学习和记忆功能。结果 GEN发挥神经保护作用的最佳剂量为1.0 mg/kg;与sham组相比,I/R组和溶剂对照组海马CA1区TUNEL阳性神经元数量显著增多(P0.01),而1.0 mg/kg GEN可显著降低缺血后TUNEL阳性神经元数量(P0.01);与I/R组相比,GEN能明显改善缺血后大鼠的空间学习和记忆能力。缺血前侧脑室给予ICI 182,780可显著降低GEN的神经保护作用(P0.01)。结论低剂量(1.0mg/kg)GEN可显著降低缺血后大鼠海马CA1区神经元损伤,改善认知功能,其分子机制可能与雌激素受体活性密切相关。     

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.     

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.     

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal-pallidal lesion

Unilateral neurotoxin lesion of rat caudate-putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal-pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl-D-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal-pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal-pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats (P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl-D-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.     

Post-ischemic administration of progesterone in rats exerts neuroprotective effects on the hippocampus

Progesterone is neuroprotective in models of focal or global ischemia when treatment starts either before the insult or at the onset of reperfusion. In these cases the steroid may act during the occurrence of the early pathophysiological events triggered by ischemia or reperfusion. As opposed to this condition, the aim of the present study was to assess the effect of delayed, post-injury administration of progesterone on the preservation of pyramidal neurons of the hippocampus of rats 21 days after been exposed to global ischemia by the four vessel occlusion model. Progesterone (8 mg/kg, i.v.) or its vehicle, were administered at 20 min, 2, 6, and 24h after the end of ischemia. At histological examination, brains of the ischemic vehicle-treated rats showed a severe reduction of the population of pyramidal neurons in the CA1 and CA2 subfields (12% and 29% remaining neurons, respectively), and a less severe neuronal loss in the CA3 and CA4 subfields of the hippocampus (68% and 63% remaining neurons, respectively), as compared to rats exposed to sham procedures. They also showed a two-fold enlargement of the lateral ventricles and 33% shrinkage of the cerebral cortex as compared to the sham group. Progesterone treatment resulted in a significant preservation of pyramidal neurons in CA1 and CA2 (40% and 62% remaining neurons), with no ventricular dilation and only a mild (12%) cortical shrinkage. Results suggest that progesterone is able to interfere with some late pathophysiological mechanisms leading both to selective neuronal damage in the hippocampal CA1 and CA2 subfields, and to shrinkage of the cerebral cortex.     

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.     

Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils

Metabolism of arachidonic acid by cyclooxygenase is one of the primary sources of reactive oxygen species in the ischemic brain. Neuronal overexpression of cyclooxygenase-2 has recently been shown to contribute to neurodegeneration following ischemic injury. In the present study, we examined the possibility that the neuroprotective effects of the cyclooxygenase-2 inhibitor nimesulide would depend upon reduction of oxidative stress following cerebral ischemia. Gerbils were subjected to 5 min of transient global cerebral ischemia followed by 48 h of reperfusion and markers of oxidative stress were measured in hippocampus of gerbils receiving vehicle or nimesulide treatment at three different clinically relevant doses (3, 6 or 12 mg/kg). Compared with vehicle, nimesulide significantly (P<0.05) reduced hippocampal glutathione depletion and lipid peroxidation, as assessed by the levels of malondialdehyde (MDA), 4-hydroxy-alkenals (4-HDA) and lipid hydroperoxides levels, even when the treatment was delayed until 6 h after ischemia. Biochemical evidences of nimesulide neuroprotection were supported by histofluorescence findings using the novel marker of neuronal degeneration Fluoro-Jade B. Few Fluoro-Jade B positive cells were seen in CA1 region of hippocampus in ischemic animals treated with nimesulide compared with vehicle. These results suggest that nimesulide may protect neurons by attenuating oxidative stress and reperfusion injury following the ischemic insult with a wide therapeutic window of protection.     

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.     

Behavioral evaluation of the anti-excitotoxic properties of MK-801: comparison with neurochemical measurements

The ability of MK-801 to protect striatal neurons from the excitotoxic action of quinolinic acid was evaluated by means of apomorphine-induced rotational behavior and by measurement of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activity, neurochemical markers for cholinergic and GABAergic neurons, respectively. Animals with a unilateral quinolinic acid lesion of the striatum exhibited a vigorous rotational response when challenged with apomorphine (0.5 mg/kg, s.c.) 6 days later and were found to have an 88 90% depletion of striatal ChAT and GAD activity. Treatment with a high dose of MK-801 (10 mg/kg, i.p.) prior to intrastriatal injection of quinolinic acid eliminated the subsequent rotational response to apomorphine and resulted in complete protection of striatal ChAT and GAD activity. Lower doses of MK-801 (1, 3 and 5 mg/kg, i.p.) failed to significantly reduce the rotational response to apomorphine but provided partial, dose-dependent protection of both ChAT and GAD activity. The rotational response to apomorphine correlated with the percent reduction in both ChAT activity (r = 0.57, P less than 0.0005) and GAD activity (r = 0.49, P less than 0.0005). Rotational behavior may thus provide a means to evaluate the functional integrity of the striatum.     

Air righting: role of the NMDA receptor channel and hippocampal LTP

Air righting results in an animal turning over when it is dropped from a height in an inverted position. In the rat, air righting is a complex set of movements that depends only on an intact labyrinth and the normal vestibular input. Visual modulation of air righting does not develop until adulthood; and the ability to estimate the time to impact requires bilateral visual cues and indicates that air righting is a complex set of perceptually controlled movements and learning. The general purpose of this study was to determine the role of the NMDA receptor-ion channel on air righting and hippocampal LTP. Specifically: to measure the effects of various doses of CPP, an NMDA receptor antagonist, and MK-801, an ion channel blocker, on (a) air righting and (b) hippocampal LTP induction in medial perforant path-granule cell synapses. The following doses were used: CPP-0, 1, 5, and 10 mg/kg i.p.; MK-801-0. 0, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg i.p. Data were analyzed by appropriate ANOVAs and post hoc tests. Results were significant and demonstrate dose-dependent impairment of air righting and inhibition of LTP for both CPP and MK-801, implicating the role of the NMDA receptor and Na(+)/K(+)/Ca(2)+ channel in these effects. Air righting is a complex behavior and appears to be dependent upon NMDA mediated hippocampal LTP.     

NMDA-Antagonist MK-801-induced neuronal degeneration in Wistar rat brain detected by the Amino-Cupric-Silver method

The neurotoxic effect following a single intraperitoneal injection of MK-801 (10 mg/kg) in adult female Wistar rats at different survival times was studied with the 1994 version of de Olmos' Amino-Cupric-Silver (A-Cu-Ag) technique for detection of neural degeneration. In addition to the well documented somatodendritic degeneration observable in cortical olfactory structures, dentate gyrus, retrosplenial and sensory cortices, we detected this type of neuronal degeneration also in the main olfactory bulb, motor and anterior cingulate cortices, thalamus and cerebellum. Terminal degeneration, not reported by previous authors, was detected in cortical olfactory structures, hippocampal formation, sensory, infralimbic, prelimbic, agranular insular, ectorhinal, perirhinal and lateral orbital cortices. These results demonstrate that the A-Cu-Ag procedure is more efficient than other silver methods for detecting the degeneration induced by MK-801. In fact, the use of the A-Cu-Ag method has made it possible to infer the connectional relations between the damaged cell bodies and corresponding terminal degeneration. Our results also indicate that the A-Cu-Ag technique may be a suitable method for the staining of neurons undergoing apoptotic-like degeneration. The probable degenerative mechanism of MK-801 in the main olfactory system is discussed.     

Dextromethorphan does not protect against quinolinic acid neurotoxicity in rat striatum

Dextromethorphan (DM, 40 or 80 mg/kg, i.p.) and MK-801 (3 or 10 mg/kg, i.p.) were compared in their ability to prevent the depletion of choline acetyltransferase (ChAT) activity in the rat striatum following intrastriatal injection of quinolinic acid. DM did not reduce striatal ChAT depletion following injection of either 300 or 150 nmol of quinolinic acid. Following injection of 300 nmol of quinolinic acid, MK-801 significantly reduced striatal ChAT depletion at a dose of 3 mg/kg and completely prevented striatal ChAT depletion at a dose of 10 mg/kg. In contrast to the potent neuroprotective action of MK-801, DM does not protect striatal cholinergic neurons from an acute challenge by an NMDA receptor agonist.     

Contribution of peripheral N-methyl-D-aspartate receptors to c-fos expression in the trigeminal spinal nucleus following acute masseteric inflammation

In this study, we examined the contribution of N-methyl-D-aspartate (NMDA) receptors on c-fos expression in the trigeminal brainstem nuclei following acute muscle inflammation. Mustard oil (MO; 20%, 30 microL) injected into the masseter muscle induced extensive peripheral edema and Fos-like immunoreactivity (Fos-LI) in several trigeminal brainstem areas including the subnucleus caudalis of the trigeminal spinal nucleus (Vc), the ventral and dorsal regions of the Vc/subnucleus interpolaris transition zone, and the paratrigeminal nucleus. In order to assess the effect of antagonizing NMDA receptors on MO-induced Fos-LI, rats were pre-treated with two different doses of i.v. MK-801 (0.3 mg/kg, 3 mg/kg), a non-competitive NMDA receptor antagonist, 30 min prior to MO injection. Additional groups of rats received MK-801 (0.3 mg/kg) directly in the masseter muscle or in the biceps muscle 5 min prior to MO injection. A higher dose of i.v. MK-801 (3 mg/kg) and MK-801 given locally into the masseter muscle (0.3 mg/kg) produced a significant reduction in total number of MO-induced Fos-LI. Further analyses revealed that pre-treatment with MK-801 (3 mg/kg i.v.) significantly reduced the Fos-LI all throughout the Vc. Only at the caudal Vc, there was a dose-dependent reduction of MO induced Fos-LI. Pre-treatment with masseteric MK-801 also significantly reduced the Fos-LI in the caudal Vc, with the effect greater than that produced by the same dose of MK-801 given intravenously. These results suggest that peripheral NMDA receptors contribute to nociceptive processing from craniofacial muscles.     

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.     

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.     

Neuroprotective effects of inhibiting N-methyl-D-aspartate receptors, P2X receptors and the mitogen-activated protein kinase cascade: a quantitative analysis in organotypical hippocampal slice cultures subjected to oxygen and glucose deprivation

Cell death was assessed by quantitative analysis of propidium iodide uptake in rat hippocampal slice cultures transiently exposed to oxygen and glucose deprivation, an in vitro model of brain ischemia. The hippocampal subfields CA1 and CA3, and fascia dentata were analyzed at different stages from 0 to 48 h after the insult. Cell death appeared at 3 h and increased steeply toward 12 h. Only a slight additional increase in propidium iodide uptake was seen at later intervals. The mitogen-activated protein kinases extracellular signal-regulated kinase 1 and extracellular signal-regulated kinase 2 were activated immediately after oxygen and glucose deprivation both in CA1 and in CA3/fascia dentata. Inhibition of the specific mitogen-activated protein kinase activator mitogen-activated protein kinase kinase by PD98059 or U0126 offered partial protection against oxygen and glucose deprivation-induced cell damage. The non-selective P2X receptor antagonist suramin gave neuroprotection of the same magnitude as the N-methyl-D-aspartate channel blocker MK-801 (approximately 70%). Neuroprotection was also observed with the P2 receptor blocker PPADS. Immunogold data indicated that hippocampal slice cultures (like intact hippocampi) express several isoforms of P2X receptors at the synaptic level, consistent with the idea that the effects of suramin and PPADS are mediated by P2X receptors. Virtually complete neuroprotection was obtained by combined blockade of N-methyl-D-aspartate receptors, P2X receptors, and mitogen-activated protein kinase kinase. Both P2X receptors and N-methyl-D-aspartate receptors mediate influx of calcium. Our results suggest that inhibition of P2X receptors has a neuroprotective potential similar to that of inhibition of N-methyl-D-aspartate receptors. In contrast, our comparative analysis shows that only partial protection can be achieved by inhibiting the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase cascade, one of the downstream pathways activated by intracellular calcium overload.