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At least 19 recordsLinked to original sources
PubMed2000

Effect of dizocilpine maleate on discriminative properties of methamphetamine in rats.

AIM: To study the effect of (+)-10, 11-dihydro-5-methyl-5H-dibenzo [a, d] cyclohepten-5, 10-imine maleate(dizocilpine maleate, MK-801) on the discriminative behavior of methamphetamine (MA). METHODS: Two lever and a fixed-ratio schedule of food presentation reinforcement program were used in discrimination test session. RESULTS: Rats can shape and maintain the discriminative behavior for MA (1 mg/kg, s.c.) and saline (1 mL/kg, s.c.). On pretreatment with dizocilpine maleate (0.1 mg/kg) in MA dependent rats, the correct discrimination percentage of MA was markedly decreased; but pretreatment with dizocilpine maleate (0.025, 0.05 mg/kg) did not block discrimination behavior of MA in antagonistic test. After injection of dizocilpine maleate (0.1 mg/kg) alone in MA dependent rats, six of the seven rats partially or completely responded on the MA associated lever whereas one did not. All of the rats had no substitution after injection of dizocilpine maleate (0.025, 0.05 mg/kg). CONCLUSION: N-methyl-D-aspartate (NMDA) receptor may be involved in psychological dependence of MA.

Animals↗
PubMed1994

Reversal of the adaptive response of neuropeptide Y neurons in the rat striatum to nigrostriatal dopamine deafferentation by the N-methyl-D-aspartate antagonist dizocilpine maleate.

This study examined the effects of systemic treatments with dizocilpine maleate alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic neurons on the number and staining intensity of neuropeptide Y-immunoreactive neurons in the rat striatum. In the combined condition, short-term and long-term treatments with dizocilpine maleate were started 19 days and 12 days after the lesion of the nigrostriatal dopaminergic pathway, respectively. As reported previously, the unilateral dopaminergic lesion elicited an increase in both the number and staining intensity of neuropeptide Y-immunoreactive neurons in the ipsilateral striatum. Short-term treatment with dizocilpine maleate at the dose of 0.2 mg/kg (four injections, 6 h apart, sacrifice 2 h after the final dose), which by itself did not modify neuropeptide Y immunostaining, totally suppressed the effect of the dopaminergic deafferentation on the number of neuropeptide Y-positive neurons but not that on the intraneuronal amount of labelling. When administered twice a day for eight days at the same dose of 0.2 mg/kg, dizocilpine maleate by itself elicited an increase in the number of neuropeptide Y-immunodetectable cells, paradoxically concomitant with a decrease in the levels of intraneuronal labelling. After combination of this treatment with unilateral lesion of the nigrostriatal dopaminergic pathway, the changes related to either the dizocilpine maleate treatment or the 6-hydroxydopamine-induced lesion totally disappeared, so that the number and staining intensity of neuropeptide Y-immunoreactive neurons in that condition did not differ from control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1998

Different neural mechanisms underlie dizocilpine maleate- and dopamine agonist-induced locomotor activity.

This study evaluated and compared the role of mesoaccumbens dopamine and the ventral pallidal region in the locomotor stimulatory action of the non-competitive N-methyl-D-aspartate antagonist dizocilpine maleate and dopamine agonists. Intra-accumbens injections of both amphetamine (1, 5 and 25 nmol) and dizocilpine maleate (1, 5, 25 and 50 nmol) induced a dose-dependent increase in locomotor activity. The N-methyl-D-aspartate antagonist was somewhat less effective than amphetamine. 6-Hydroxydopamine dopamine-depleting lesions of the nucleus accumbens completely blocked locomotor stimulation induced by focal administrations of amphetamine (5 nmol), but were ineffective in altering the actions of dizocilpine maleate (50 nmol). Ibotenic acid lesions of the ventral pallidal region and muscimol injections into this area also prevented the stimulatory effects of systemic amphetamine (1 mg/kg), while having no effect on the locomotor-activating actions of systemic dizocilpine maleate (0.3 mg/kg). Microdialysis studies revealed that systemically administered apomorphine (2 mg/kg) significantly decreased extracellular GABA in the pallidum, which was accompanied by substantial increases in locomotor output. Systemically administered dizocilpine maleate (0.3 mg/kg), on the other hand, also increased locomotor activity without having any effect on pallidal GABA. These data, taken together, indicate that while the locomotor effects of dopamine agonists are dependent upon intact mesoaccumbens dopamine and involve GABAergic efferents from the nucleus accumbens to the ventral pallidum, dizocilpine maleate's stimulatory actions are independent of such mechanisms.

Amphetamine↗
PubMed2006

Therapeutic effect of hypothermia and dizocilpine maleate on traumatic brain injury in neonatal rats.

This study was undertaken to evaluate the therapeutic effect of hypothermia and dizocilpine maleate in traumatic brain injury (TBI) on newborn rats. After induction of TBI, physiologic and histopathological assessments were performed on both the control and therapeutic groups to evaluate the effects of both agents. Rats were assigned into four groups as follows: normothermic (n = 23), hypothermic (n = 18), normothermia plus dizocilpine maleate (n = 18) and hypothermia plus dizocilpine maleate (n = 18). All the rats were injured using a weight-drop head injury model, artificially ventilated with a 33% O(2) and 66% NO(2) mixture, and physiological parameters, intracranial pressure, and brain and rectal temperatures were recorded. Mortality, physiological, neurological parameters, and histopathological changes were assessed after 24 h. As a result, intracranial pressure, cerebral perfusion pressure, morbidity, weight loss, and microscopic changes were significantly worse in the normothermic group (p <0.05). There was no statistical difference between other groups (p > 0.05). Hypothermia and dizocilpine maleate displayed similar neuroprotective effects in TBI on newborn rats, but no additive effect was observed.

Animals↗
PubMed1995

Chronic treatment with dizocilpine maleate increases the number of striatal neurons expressing the D2 receptor gene.

N-methyl-D-aspartate antagonists have been proposed as potential therapeutic agents in different neurological diseases, including Parkinson's disease. The effects of gene expression of a chronic treatment with the non-competitive N-methyl-D-aspartate antagonist, dizocilpine maleate (0.8 mg/kg day, per os for 50 days) were analysed in rat striata. Using quantitative in situ hybridization, we measured the messenger RNA expression of the genes encoding D1, D2 dopamine receptors, N-methyl-D-aspartate receptor 1 subunit of N-methyl-D-aspartate receptor, preproenkephalin A and substance P. Chronic treatment with dizocilpine maleate induced a moderate but significant increase in messenger RNA of the N-methyl-D-aspartate receptor 1 subunit in the striatum and the adjacent cortex, suggesting an action of dizocilpine maleate in these two regions. This treatment did not induce any change in D1 receptor, preproenkephalin A or substance P messenger RNA content in the striatum, whereas D2 receptor messenger RNA was increased in the striatum of treated rats. Microscopic analysis revealed that it was the number of medium-sized neurons expressing D2 receptor messenger RNA that was significantly enhanced, while the mean amount of message per cell remained unchanged. These results demonstrate that glutamate via N-methyl-D-aspartate receptors, regulates the D2 receptor gene in striatal neurons. A chronic treatment with dizocilpine maleate increases the number of striatal neurons expressing the D2 receptor gene, suggesting a recruiting phenomenon.

Animals↗
PubMed1996

Chronic dizocilpine maleate (MK-801) treatment suppresses the effects of nigrostriatal dopamine deafferentation on enkephalin but not on substance P expression in the rat striatum.

The present study examined the effects of chronic treatment with dizocilpine maleate (0.2 mg/kg i.p., twice a day for 8 days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic neurons on substance P and enkephalin expression in the rat striatum. This was done by means of quantitative in situ hybridization histochemistry and immunocytochemistry. As reported previously, the unilateral dopaminergic lesion resulted in marked decreases in substance P mRNA expression and immunoreactivity in the ipsilateral striatum while enkephalin mRNA expression and Met-enkephalin immunoreactivity were considerably increased in this structure. Blockade of NMDA receptors by chronic dizocilpine maleate treatment alone resulted in decreased levels of striatal substance P mRNA without significant change in substance P immunoreactivity versus controls. Enkephalin mRNA levels were also decreased in the striatum, matched by parallel reductions in Met-enkephalin immunoreactivity. These observations indicate that NMDA receptor activity may exert tonic excitatory effects on substance P and enkephalin expression in the striatum. The same chronic treatment with dizocilpine maleate started 12 days after the 6-hydroxydopamine injection suppressed the lesion-induced up-regulation of enkephalin expression without significantly affecting the down-regulation of substance P expression. These data provide evidence that NMDA receptor-mediated mechanisms contribute to the alteration of striatal enkephalin expression associated with dopaminergic depletion in hemiparkinsonian rat models.

Afferent Pathways↗
PubMed1998

Effect of desmethyl tirilazad, dizocilpine maleate and nimodipine on brain nitric oxide synthase activity and cyclic guanosine monophosphate during cerebral ischemia in rats.

The present study was designed to evaluate the effects of pretreatment with a combination of desmethyl tirilazad (21-aminosteroid) plus dizocilpine maleate (N-methyl-D-aspartate receptor antagonist) and nimodipine (calcium channel antagonist) on constitutive nitric oxide synthase (cNOS) activity and cyclic guanosine monophosphate (cGMP) levels in brain homogenates of rats subjected to global cerebral transient ischemia induced by bilateral clamping of the carotids for 30 min and reduction of arterial pressure (to 50-60 mm Hg) by intravenous infusion of trimethaphan (30 mg/kg). Our results show that cerebral ischemia produced an increase in cNOS activity and cGMP levels in brain homogenates. Pretreatment with desmethyl tirilazad or dizocilpine maleate or nimodipine individually significantly suppressed (p < 0.01) the increase in cNOS activity and cGMP levels induced by cerebral ischemia, which may be related to their neuroprotective effect. Similar results were obtained with pretreatment by a combination of desmethyl tirilazad plus dizocilpine maleate plus nimodipine.

Animals↗
PubMed1996

Repeated injections of dizocilpine maleate (MK-801) do not suppress the effects of nigrostriatal dopamine deafferentation on glutamate decarboxylase (GAD67) mRNA expression in the adult rat striatum.

The present study examined the effects of glutamate transmission blockade through N-methyl-D-aspartate (NMDA) receptor subtype by repeated administration of dizocilpine maleate (0.2 mg/kg. i.p., twice a day for eight days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic pathway on GABAergic neurons in the adult rat striatum. For this purpose, the expression of the messenger RNA encoding for the 67 kDa isoform of the GABA synthesizing enzyme, glutamate decarboxylase (GAD67 mRNA), was studied in the various conditions by quantitative in situ hybridization. The dizocilpine maleate treatment alone did not induce significant change of GAD67 mRNA levels in the striatum, indicating that NMDA receptors may not have a major role in the transcriptional regulation of GAD67 in the adult rat striatum. As reported previously, the unilateral dopaminergic lesion resulted in marked increases in GAD67 mRNA levels in the ipsilateral striatum. This up-regulation was not significantly affected by the treatment with dizocilpine maleate started 12 days after the unilateral intranigral 6-hydroxydopamine injection. Therefore, NMDA receptors are unlikely to contribute to the dopamine lesion-induced GAD67 mRNA up-regulation in striatal projection neurons. This result is of major interest in comparison with our previous finding that NMDA receptor activation is necessary to maintain the up-regulation of enkephalin expression in the striatum after dopamine lesion.

Animals↗
PubMed2002

Altered responses to dizocilpine maleate administration in ethanol-withdrawn male and female rats.

Dizocilpine maleate (MK-801) is a highly potent, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Although it has been suggested that dizocilpine may be beneficial in alleviating some symptoms of ethanol withdrawal, a rigorous evaluation of beneficial versus detrimental (phencyclidine-like) actions has not been done. The objective of the present investigation was to explore whether dizocilpine protects against ethanol withdrawal-induced increases in seizure susceptibility without being compromised by its phencyclidine-like behavioral actions. The effects of dizocilpine were assessed by using seizure threshold determinations and scoring of open field behaviors. Low dose dizocilpine administration preferentially protected against bicuculline seizure induction in ethanol-withdrawn female rats when compared with findings in ethanol-withdrawn male rats. In contrast, we found dramatic reductions in dizocilpine-induced open field behaviors during ethanol withdrawal in both male and female rats compared with findings for pair-fed control animals. [3H]MK-801 binding analysis ruled out changes in cerebral cortex or hippocampus receptor density or affinity as having a primary role in these differential responses. Taken together, our findings from these studies indicate that there are complex neuroadaptations in NMDA receptor systems after persistent ethanol exposure, manifested as either enhanced or reduced responses, depending on the measure used.

Animals↗
PubMed1997

Quantitative autoradiography of 5-[3H]6-cyano-7-nitro-quinoxaline-2,3-dione and (+)-3-[3H]dizocilpine maleate binding in rat vestibular nuclear complex after unilateral deafferentation, with comparison to cochlear nucleus.

The distributions of non-N-methyl-D-aspartate and N-methyl-D-aspartate receptors in the rat vestibular nuclear complex were estimated by quantitative autoradiography of 5-[3H]6-cyano-7-nitro-quinoxaline-2,3-dione and (+)-3-[3H]dizocilpine maleate binding, respectively. The binding of 5-[3H]6-cyano-7-nitro-quinoxaline-2,3-dione in the vestibular nuclear complex was also compared with that in the cerebellar cortex and cochlear nucleus. Measurements were made in control rats and in rats with unilateral destruction of the inner ear and removal of the vestibular ganglion. Compared to the unlesioned side, 5-[3H]6-cyano-7-nitro-quinoxaline-2,3-dione binding in the lesioned-side vestibular nuclear complex was decreased significantly in all regions at two to four postoperative days. However, the bilateral asymmetry disappeared in most regions by 30 days. 5-[3H]6-Cyano-7-nitro-quinoxaline-2,3-dione binding increased in the molecular layer of the cerebellar cortex at 30 days after lesion, although there were no clear changes at two to seven days. 5-[3H]6-Cyano-7-nitro-quinoxaline-2,3-dione binding in the cochlear nucleus decreased on the lesioned side, compared to the unlesioned side, in regions receiving significant auditory nerve innervation, but increased in the molecular layer of the dorsal cochlear nucleus. (+)-3-[3H]Dizocilpine maleate binding in regions of the vestibular nuclear complex was reduced on the lesioned side, compared to the unlesioned side, after deafferentation, with the largest reductions usually at 30 postoperative days. It is suggested that: (i) non-N-methyl-D-aspartate receptors are involved in synaptic transmission for both vestibular and auditory nerve fibers, while the involvement of N-methyl-D-aspartate receptors is less certain; (ii) unilateral deafferentation of the vestibular nuclear complex can result in bilateral asymmetries for non-N-methyl-D-aspartate and N-methyl-D-aspartate receptors, which are most prominent at earlier and later survival times, respectively; and (iii) vestibular compensation may involve regulation of both non-N-methyl-D-aspartate and N-methyl-D-aspartate receptors in the vestibular nuclear complex and activation of non-N-methyl-D-aspartate receptor-related processes in cerebellar cortex.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Effect of dizocilpine maleate on cerebral anoxia and ischemic damage in rodents.

The Protective effects of dizocilpine maleate (DM) against anoxia in mice and ischemic damage in rats of 4-vessel occlusion (4-VO) were studied. DM 0.5 or 1.0 mg.kg-1 ip significantly prolonged the survival time of mice in closed containers. DM 0.5 and 1.0 mg.kg-1 ip 30 min prior to 4-VO obviously accelerated the electroencephalographic recovery, reduced the neuronal loss in the hippocampus, and increased the survival rate after 72-h reperfusion. These effects followed a dose-dependent manner. Our results indicate that selective non-competitive N-methyl-D-aspartate receptor blocker DM protects against anoxic and ischemic cerebral damage.

Animals↗
PubMed1992

Effect of dizocilpine maleate on monoamines and their metabolites in rat brain.

Systemic (ip) injection of dizocilpine maleate (DM, 0.1 and 0.5 mg.kg-1) increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid but did not bring about any noticeable change in the dopamine (DA) level in the striatum and limbic area. DM also increased the levels of norepinephrine in the limbic area and 5-hydroxyindoleacetic acid in the hippocampus. Amphetamine increased DA level and reduced DOPAC level in the striatum and limbic area. The behavioral manifestations revealed that DM predominantly evoked circling behavior and ataxia. The results indicate that the mechanism of the behavioral effect of DM may be different from that of amphetamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex.

MK(+)801 (dizocilpine maleate) is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, the major glutamate receptor at excitatory synapses in the central nervous system. Since NMDA antagonists are neuroprotective, there is interest in their development for treatment of cerebral ischemia. Unfortunately, many of these compounds also induce vacuole formation in neurons of the rat retrosplenial cortex (Olney et al., Science 244: 1360-1362, 1989). Although vacuolization was initially reported to be reversible with MK(+)801, preliminary data later suggested that higher doses might produce neuronal necrosis. To explore this issue, young male Sprague-Dawley rats were given a single subcutaneous dose of vehicle or 1, 5, or 10 mg/kg MK(+)801. At 4 h and 1, 2, 3, 4, 7, and 14 days postdose (DPD), the retrosplenial cortex was examined by light and electron microscopy. At 4 h, vacuoles occurred in neurons of retrosplenial cortical layers 3 and 4 in all rats given MK(+)801. Mitochondria and endoplasmic reticulum contributed to vacuole formation. At 1 DPD, vacuoles or necrotic neurons were rarely observed. At all subsequent time points, necrotic neurons were readily evident in rats given 5 or 10 mg/kg MK(+)801, but only rarely evident in rats given 1 mg/kg. Necrotic neurons were associated with reactive microglial cells that contained electron-dense debris ultrastructurally. If similar dose-dependent neuronal necrosis proves to be a feature of other NMDA antagonists, such effects might raise concerns for the development and use of these compounds in human cerebrovascular diseases.

Animals↗
PubMed1994

Intrathecal administration of dizocilpine maleate (MK-801) attenuates ischemic damage in the rabbit spinal cord.

The therapeutic efficacy of intrathecally administered MK-801 (dizocilpine maleate), a noncompetitive receptor antagonist of N-methyl-D-aspartate receptor complex, was investigated in a rabbit spinal cord ischemia model. Normal saline, 0.3 ml (control, n = 4) or MK-801, 150 micrograms in 0.3 ml of saline, was administered intrathecally at the level of the lumbar enlargement, 30 min before (pretreatment, n = 7) or in the first min after (post-treatment, n = 4) 30 min of aortic occlusion followed by 2-h reperfusion. Nauta silver method was used for histopathological evaluation of lumbosacral segments. The degree of gray matter damage (argyrophilic neurons) was evaluated in three areas: A1, Rexed's laminae I-VI; A2, laminae VII and X; and A3, laminae VIII-IX. Pre- and post-treatment with MK-801 decreased the number of argyrophilic neurons (P < 0.05) in all areas examined. The number of argyrophilic neurons in A1, A2, and A3 was reduced by 59, 28, and 29%, respectively, by MK-801 pretreatment and by 87, 66, and 46%, respectively, by MK-801 post-treatment. Our results show that with single bolus intrathecal administration the efficacy of MK-801 was greater with post- compared to pretreatment and most dramatic in Rexed's laminae I-VI compared to laminae VII-X. Intrathecal administration of MK-801 prior to or at the beginning of the recirculation diminishes the extent of postischemic neuronal spinal cord damage at early postreperfusion period.

Animals↗
PubMed1997

Pre- and postischemic effects of the NMDA receptor antagonist dizocilpine maleate (MK-801) on collateral cerebral blood flow.

The authors studied the effects of pre- and postischemic administration of dizocilpine maleate (MK-801) on collateral and regional cerebral blood flow (CBF). The ischemic penumbra appears to benefit most from the neuroprotective effects of MK-801. The precise mechanism by which MK-801 provides this neuroprotection remains controversial. Alterations in CBF have been demonstrated with MK-801 administration, but whether the response is an increase or decrease in flow has remained unclear. A left-sided craniectomy was performed in 20 dogs. A branch of the middle cerebral artery (MCA) was cannulated and collateral blood supply-dependent tissue (CDT) was identified using the "shadow flow" technique. Regional CBF was measured using radiolabeled microspheres. Six dogs received MK-801 (1 mg/kg administered intravenously) before they underwent MCA branch occlusion; the remaining 14 dogs received MK-801 after they underwent MCA occlusion. Cerebral blood flow and vascular pressures were measured 30 and 60 minutes after MK-801 administration. In animals that received MK-801 before MCA occlusion, CBF did not change significantly from baseline values before or after occlusion. In contrast, in animals that received MK-801 after MCA occlusion, CBF was significantly reduced in all regions of the brain, including the CDT. Collateral blood supply-dependent tissue showed a 51.7% reduction in flow, whereas normal CBF was reduced by 29.7%. The MK-801 induced cerebral vasoconstriction in both groups. The neuroprotective effects of MK-801 do not appear to be caused by the augmentation of collateral or global cerebral circulation and, in fact, may block the glutamate-mediated vasodilation that occurs during ischemia.

Animals↗
PubMed1995

Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia.

The present study was inspired by two previous findings from the laboratory. The first was that dizocilpine maleate (MK-801) fails to reduce infarct size when the middle cerebral artery (MCA) is permanently occluded by an intraluminal filament technique in rats. In seeking the reasons for this we measured temperature and found that the body temperature of occluded animals increases to 39.0-39.5 degrees C during the first 2-3 h. In order to explore whether the rise in temperature was responsible for the lack of effect of MK-801, two groups of animals were studied, both containing animals which were subjected to 2 h of transient MCA occlusion and given MK-801 15 min before, as well as 6 and 24 h after ischemia. In one group, temperature was allowed to rise spontaneously during ischemia (39.0-39.5 degrees C). In the other, body temperature was maintained close to normal during ischemia, and for the first 6 h postischemically, by cooling of the ambient air. Infarct volume was assessed by triphenyltetrazolium chloride staining after 48 h of recovery. The results showed that MK-801 failed to reduce infarct size in animals whose body temperature rose during ischemia. In contrast, the drug markedly reduced infarct volume in temperature-controlled animals; in fact, 5/8 animals had no infarcts but selective neuronal damage only. The results suggest that amelioration of focal ischemic damage cannot be expected if body and brain temperature is allowed to rise above normal.

Animals↗
PubMed1990

The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates.

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 micrograms/kg i.v. over 5 min, followed by an infusion of 150 micrograms/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups (p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.

Animals↗
PubMed1994

Blockade of N-methyl-D-aspartate receptors by MK-801 (dizocilpine maleate) rescues motoneurones in developing rats.

In rats following nerve injury at birth a large proportion of motoneurones to the soleus muscle dies. Blocking of N-methyl-D-aspartate (NMDA) receptors by MK-801 (dizocilpine maleate) for 12 days after nerve injury at birth leads to rescue of a proportion of motoneurones destined to die. Retrograde labelling of soleus motoneurones shows that 6-8 weeks after crushing the sciatic nerve in one hindlimb, only 10.9 +/- 2.3% of the motoneurones have survived. In animals treated with an NMDA receptor blocker MK-801 (2 mg/kg i.p., from birth to 12 days old) 50.6 +/- 3.8% of soleus motoneurones survived. This neuroprotective effect of MK-801 was dose dependant, since after treatment with lower doses (0.5 mg/kg; 1 mg/kg) fewer motoneurones survived (13.7% and 34.5%, respectively). To assess the effect of treatment with MK-801 on survival of alpha-motoneurones only, the number of soleus motor units was established physiologically. After nerve injury alone only 4.2 +/- 1.2 of the 29-30 soleus motor units were present, while in animals treated with MK-801 (2 mg/kg) 14 +/- 1.5 motor units were identified. The neuroprotective effect of MK-801 was not confined to soleus motoneurones but was also apparent on motoneurones to the extensor digitorum longus (EDL). In untreated EDL muscles of the 40 motor units only 5.5 +/- 1.7 motor units survived neonatal nerve injury and this number increased to 18 +/- 2.6 after treatment with MK-801. The neuroprotective effect of MK-801 was apparent regardless of whether the nerve lesion was carried out close to or far from the soleus muscle.

Animals↗