Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study assessed the ability of N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), to modulate neonatal cocaine-induced neurobehavioral changes in the rat. Sprague-Dawley rats were randomly assigned on postnatal day 0 (PND 0) to one of four treatment groups. Treatments began on PND 4 and continued until PND 10. Treatments consisted of an oral bolus of either cocaine HCl (40 mg/kg), (+)MK-801 (0.4 mg/kg), (+)MK-801 (0.4 mg/kg) followed 30 min later with cocaine HCl (40 mg/kg) or 0.9% saline. On PND 21, 30, 40 and 60, males and females were examined for stress response using the cold-water swim test. Cocaine-treated male and female rats exhibited significantly diminished tolerance to cold-water stress compared to control and MK-801/cocaine-treated groups. In addition, neonatal exposure to cocaine was associated with increased severity of motor symptoms (tail twitches, wet dog shaking and convulsions) following the administration of NMDA (35 mg/kg). Treatment groups were also tested for pain sensitivity using the tail flick (TF) and hot plate (HP) methods. The results indicated that neonatal cocaine exposure altered pain sensitivity in both tests. NMDA receptor binding studies showed a significant increase in receptor densities in the hippocampus and hypothalamus of the cocaine-treated group compared to control. MK-801 administered to rat pups before cocaine treatment blocked the increase in receptor density. The results indicated that neonatal cocaine exposure was associated with altered responses to NMDA, stress tolerance and pain sensitivity. Moreover, the pretreatment with NMDA receptor antagonist, MK-801, abolished or attenuated these cocaine-induced neurobehavioral changes.
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PMID:The role of NMDA receptors in neonatal cocaine-induced neurotoxicity. 1150 4

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight-day-old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31-day-old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre-treatment with the NMDA receptor antagonist MK-801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.
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PMID:Delayed white matter injury in a murine model of shaken baby syndrome. 1214

Although the antinociceptive effect of NMDA antagonists in the formalin test is well recognised, these compounds can induce adverse motor effects. The aim of this study was to identify the systemic doses of NMDA antagonists that induce analgesia without causing side effects. Male Swiss mice (30-40g) received a subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface of the right hind-paw and, 15min before or after formalin, an ip injection of one of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg), memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg), dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain-related behaviour (licking, lifting, favouring, shaking, and flinching of the treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor antagonists significantly (p<0.01) and dose-dependently reduced, versus controls, nociceptive activity during the second phase of the formalin test (from the 20th to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and 80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order potency of antinociceptive activity of NMDA antagonists was: MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists administered after formalin (during the analgesic interval) did not affect the late phase of the formalin test. In conclusion, systemic administration of NMDA receptor antagonists decreases the nociception observed during the late phase of the formalin test.
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PMID:Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test. 1260 Jul 94

This study examined the nociceptive effects of the intrathecal administration of various doses of the following endogenous excitatory sulphur-containing amino acids (SAAs): L-cysteic acid (L-CA), L-cysteine sulfinic acid (L-CSA), L-homocysteic acid (L-HCA) and L-homocysteic sulfinic acid (L-HCSA). For a period of 10min, rats were observed for spontaneous nociceptive behaviours (SNBs), including: tail elevation, twitching or licking; hindpaw elevation, licking or shaking; and caudally directed biting or scratching. The amount of time each rat spent eliciting these individual behaviours was recorded and a total time (in seconds) spent exhibiting SNBs was then calculated. To determine which glutamate receptors are primarily responsible for these nociceptive behaviours, we pretreated additional groups of rats with selective antagonists for N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid/kainate (AMPA/KA) and group I metabotropic glutamate receptors (mGluR1 and 5). Results indicate that SAAs dose-dependently produce SNBs that are attenuated by NMDA receptor and group I mGluR antagonists.
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PMID:Nociceptive effects of intrathecal administration of sulphur-containing amino acids. 1294

The antisense approach and RT-PCR were used to study the effects of muscarinic receptors on the scores of morphine-withdrawal syndrome and the expression of NMDA receptor subtypes (NR(1A) and NR(2A)) mRNA in rat spinal cord and brainstem. The concentrations of glutamate in periaqueductal grey (PAG) of morphine-withdrawal rats were determined by capillary electrophoresis with laser-induced fluorescence detection. The data showed that the NR(1A) and NR(2A) mRNA levels were increased significantly in the spinal cord and brainstem 1 h after the injection of naloxone (4 mg/kg, i.p.) in morphine-dependent rats. Moreover, in morphine-dependent rats pretreated (i.p.) with scopolamine (0.5 mg/kg), or pirenzepine (10 mg/kg), MK801 (0.125 mg/kg), L-N-nitroarginine methylester (10 mg/kg) 30 min before naloxone injection, the NR(1A) and NR(2A) mRNA levels were significantly lower than those of 1 h morphine-withdrawal rats. Intrathecal injection of NR(1A) or M(2) receptor antisense oligonucleotides (A-oligo, 4 microg/per rat) 24 h prior to naloxone challenge could block the morphine withdrawal symptoms including wet dog shaking, irritability, salivation, diarrhea, chewing and weight loss. Meanwhile, in morphine-dependent rats the NR(1A) mRNA levels in the spinal cord and brainstem were down-regulated by intrathecal injection of M(2) receptor A-oligo. The glutamate concentrations in PAG microdialysis were increased to a maximal level 15 min after naloxone injection. The glutamate response was inhibited by pretreatment with M(2) receptor A-oligo but not by M(1) A-oligo. The results suggest that the expression of NMDA receptors and the release of glutamate in brainstem are involved in the processes of morphine withdrawal and that the NMDA receptor expression is possibly regulated by the muscarinic receptors during morphine withdrawal.
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PMID:[Muscarinic receptors modulate the mRNA expression of NMDA receptors in brainstem and the release of glutamate in periaqueductal grey during morphine withdrawal in rats]. 1498 37

The potential polyamine antagonist action of N1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N1-dansyl-spermine (2-10 microg, i.c.v.) with spermine (100 microg, i.c.v.) resulted in a dose-dependent antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N1-dansyl-spermine antagonised spermine's enhancement of NMDA-induced convulsions. These results suggest that N1-dansyl-spermine is in vivo a potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.
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PMID:N1-dansyl-spermine: a potent polyamine antagonist. 1514 Jun 45

To better understand outcomes after early brain injuries, studies must address multiple variables including age at injury, the mechanisms and severity of injury, environmental factors (before and after injury) and developmental factors. Animal models are helpful for elucidating these different aspects. First, this paper describes a new model of shaken baby syndrome (SBS) in mice, without impact or hypoxia. Mortality was 27%; 75% of survivors had focal brain lesions consisting of haemorrhagic or cystic lesions of the white matter, corpus callosum and cerebellum. All shaken animals, with and without focal lesions, showed delayed white matter atrophy. White matter damage and atrophy were reduced by pre-treatment with an NMDA receptor antagonist, indicating that excess glutamate release contributed to the pathophysiology of the lesions. Secondly, it discusses data on neuroprotection after early brain injuries; drugs targeting the NMDA receptors cannot be used in clinical practice but indirect neuroprotection strategies including anti-NO, anti-free radicals and trophic factors hold promise for limiting the excitotoxic white matter damage induced by early injury, in particular caused by shaking, during brain development. Thirdly, it describes two experimental models in which SBS outcomes are determined when the trauma is combined with environmental influences, namely medications during the acute phase, most notably anti-epileptic drugs and rearing conditions.
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PMID:Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury. 1520 68

The LDL receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor that is highly expressed on neurons. Neuronal LRP1 in vitro can mediate ligand endocytosis, as well as modulate signal transduction processes. However, little is known about its role in the intact nervous system. Here, we report that mice that lack LRP1 selectively in differentiated neurons develop severe behavioral and motor abnormalities, including hyperactivity, tremor, and dystonia. Since their central nervous systems appear histoanatomically normal, we suggest that this phenotype is likely attributable to abnormal neurotransmission. This conclusion is supported by studies of primary cultured neurons that show that LRP1 is present in close proximity to the N-methyl-D-aspartate (NMDA) receptor in dendritic synapses and can be coprecipitated with NMDA receptor subunits and the postsynaptic density protein PSD-95 from neuronal cell lysates. Moreover, treatment with NMDA, but not dopamine, reduces the interaction of LRP1 with PSD-95, indicating that LRP1 participates in transmitter-dependent postsynaptic responses. Together, these findings suggest that LRP1, like other ApoE receptors, can modulate synaptic transmission in the brain.
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PMID:Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. 1545 62

Nerve agent poisoning is characterized by the rapid progression of toxic signs, including hypersecretions, tremor, convulsions and profound brain damage. In the political arena of today's world, the threat of nerve agent use against military troops has prompted armies to search for prophylactic protection. The two main strategies for prophylaxis include biological scavengers that can bind or cleave nerve agents before they react with acetylcholinesterase, and antidotes as prophylactic treatment. Pyridostigmine is the current pretreatment for nerve agent poisoning and is in use by most of the armed forces in Western countries. However, since pyridostigmine barely crosses the blood-brain barrier it provides no protection against nerve agent-induced central injury. Pyridostigmine is ineffective when administered without post-exposure treatment adjuncts. Therefore, other directions for prophylactic treatment should be explored. These include combinations of carbamates (reversible AChE inhibitors) and central anticholinergics or NMDA receptor antagonists, benzodiazepines or partial agonists for benzodiazepine receptor, and other central AChE inhibitors approved for Alzheimer's disease. The transdermal route is an alternative way for delivering the prophylactic agent. Administration of prophylaxis can be extended also for civilian use during wartime.
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PMID:Pharmacologic prophylaxis against nerve agent poisoning. 1579 66

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.
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PMID:Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. 1583 70


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