Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Memantine, used as a drug for treatment of spasticity and other extrapyramidal disorders as well as dementia, was shown to prevent brain damage caused by the glutamate (N-methyl-D-aspartate, NMDA) receptor agonist, quinolinic acid. Studies were focused on the hippocampal formation which is known to be highly vulnerable to quinolinate. Pretreatment of animals with memantine added to the food led to a reliable protection of hippocampal neurons when the drug was administered chronically for a period of 10 days prior to quinolinate exposure (i.c.v. injected). Additional i.p. administration of memantine (simultaneously with quinolinic acid or up to 24 h later) did not substantially add to the protective potency of the memantine diet. Our findings indicate that memantine may have beneficial effects in the treatment of brain disorders which are mediated by excitotoxic effects of glutamate.
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PMID:Memantine prevents quinolinic acid-induced hippocampal damage. 142 71

After incubation of rat cortical cell cultures with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 12 h, cells showed fragmentation of DNA at internucleosomal linkers, the characteristic feature of apoptosis. In a quantitative approach, it was determined that the percentage of DNA fragmentation increased from 7%, in the absence of gp120, to 62% following incubation with 24 ng/ml of gp120. Simultaneously, the percentage of viable cells decreased from 94% to 33%. Memantine (1-amino-3,5-dimethyladamantane), a drug currently used in the therapy of spasticity and Parkinson's disease as well as the NMDA antagonist MK-801 both prevented the effects of gp120 at micromolar concentrations. In human cultured astrocytes, gp120 was ineffective with respect to DNA fragmentation and cell toxicity. From these data, we conclude that the gp120-induced apoptosis may contribute to the neurological complications frequently associated with the immunodeficiency syndrome. The cytoprotective effect of memantine in cortical cell cultures may qualify the drug for the treatment of AIDS-related dementia.
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PMID:gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine. 142 20

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with therapeutic potential in dementia, spasticity and Parkinson's disease. The Ki-value of memantine at the phencyclidine (PCP) binding site of the NMDA receptor is 0.5 microM in human frontal cortex. We investigated whether concentrations of memantine in cerebrospinal fluid (CSF) and serum samples under therapeutic conditions are in the range of its Ki-value at the PCP binding site. The serum levels ranged from 0.025 to 0.529 microM with daily doses between 5 and 30 mg. CSF levels were highly correlated to serum levels and were below serum levels in each patient with a mean CSF/serum ratio of 0.52. Serum and CSF levels were correlated to the daily dose, but not to the duration of treatment. At the concentrations reported here, memantine is expected to specifically interact with the PCP binding site of the NMDA receptor.
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PMID:Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. 747 69

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.
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PMID:Assessment of primary neuronal culture as a model for soman-induced neurotoxicity and effectiveness of memantine as a neuroprotective drug. 749 76

Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and beta-adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to 14C-memantine in the microM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 microM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol-stimulated cAMP-response without affecting beta-adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysosomotropic drug.
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PMID:Evidence for lysosomotropism of memantine in cultured human cells: cellular kinetics and effects of memantine on phospholipid content and composition, membrane fluidity and beta-adrenergic transmission. 829 47

The 1-aminoadamantanes memantine (1-amino-3,5-dimethyl-adamantane) and amantadine (1-amino-adamantane) are clinically used as anti-parkinsonian, anti-spasticity, anti-dementia and antiviral drugs. In the present investigation we have tested a series of 1-aminoadamantane derivatives including memantine and amantadine for their ability to compete with [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. The Ki values ranged from 0.237 +/- 0.019 microM for 1-N-dimethyl-amino-3,5-dimethyl-adamantane to 20.25 +/- 16.48 microM for amantadine. The Ki value of memantine was 19.98 +/- 3.08 microM and was thus very similar to that of amantadine. Memantine, at therapeutic concentrations, probably does not interact with the sigma binding site. Amantadine, at therapeutic concentrations, probably binds both to the sigma site and to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor.
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PMID:Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex. 830 17

Incubation of highly enriched neurons from rat cerebral cortex with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 18 h results in fragmentation of DNA at internucleosomal linkers, a feature of apoptosis. We report that neurons respond to exposure to gp120 with an increased release of arachidonic acid via activation of phospholipase A2. This process is not inhibited by antagonists of the N-methyl-D-aspartate (NMDA) receptor channels. To investigate the influence of arachidonic acid on the sensitivity of NMDA receptor towards its against, low concentrations of NMDA were coadministered with arachidonic acid. Under these conditions the NMDA-mediated cytotoxicity was enhanced. We conclude that gp120 causes an activation of phospholipase A2, resulting in an increased release of arachidonic acid which in turn sensitizes the NMDA receptor. Two compounds were found to act cytoprotectively against the deleterious effect caused by gp120 on neurons: Memantine [1-amino-3,5-dimethyladamantane] and Flupirtine [2-amino-3-ethoxycarbonylamino-6-(4-fluoro-benzyl-amino)-pyridine maleate]. Both compounds have been found to display a potent cytoprotective effect on neurons treated with the excitatory amino acid NMDA or with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. The NMDA antagonist Memantine, a drug currently used in the therapy of spasticity and Parkinson's disease, prevented the effects of gp120 at micromolar concentrations. Flupirtine was previously found to be a centrally acting, nonopiate analgesic agent which additionally possesses anticonvulsant and muscle-relaxant activity at doses similar to those producing analgesia. The cytoprotective effect of Flupirtine in vitro was significant (above 10 microM). Considering the fact that both Memantine and Flupirtine display almost no clinical side effects, these drugs may prove useful both in preventing primary infection of brain cells with the HIV virus, as well as in treating the neurological disorders often associated with the immunodeficiency syndrome such as AIDS-related dementia.
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PMID:Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. 882 91

Excessive accumulation of glutamate or other excitatory amino acids and the subsequent overactivity of NMDA receptors is currently thought to lead to neuronal injury in cerebral ischemia. Therefore, antagonists of the NMDA receptor may offer an approach for the treatment of ischemic brain injury. Dizocilpine (MK-801), an NMDA receptor-associated channel blocker, protects neurons in several rodent stroke models. However, this drug has numerous side effects and causes apoptosis of neonatal neurons. Recently, another NMDA receptor-associated channel blocker, memantine, has been shown to ameliorate NMDA-receptor mediated neurotoxicity in neuronal cell cultures and in focal cerebral ischemia models in adult rats without substantial side effects. Memantine has been used clinically in the treatment of Parkinson's disease and spasticity for a number of years. Here we tested the effects of memantine on focal stroke caused by photochemical thrombosis in neonatal rats and demonstrated a neuroprotective effect of memantine in this model. We also found excellent correlation between infarct size determined by magnetic resonance imaging (MRI) and histopathological analysis in the same animals. A single pre-ischemic dose of memantine (20 mg/kg) given 15 min prior to induction of stroke reduced the infarct size by 36.3% when compared to control animals treated with normal saline (P < 0.0001). At this dosage, memantine manifests few, if any, neurobehavioral side effects. Thus memantine appears to be both safe and effective in neonatal as well as adult animal models of stroke.
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PMID:Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat. 1044 69

Memantine is an uncompetitive N-methyl-D: -aspartate (NMDA) receptor antagonist. Unlike other NMDA antagonists, it has been used clinically for years for the treatment of Parkinson's disease, spasticity, and dementia without serious side effects. We aimed to investigate the therapeutic efficacy of memantine on a closed head trauma model. A total of 132 adult male Sprague-Dawley rats were randomly divided into four groups: sham-operated, control (closed head trauma), sham-vehicle (closed head trauma + saline), treatment (closed head trauma + memantine, 10 mg/kg, i.p.). A cranial impact was delivered to the skull, just in front of the coronal suture, over the left hemisphere, from the height of 7 cm. Saline or memantine were applied 15 min after trauma. Rats were euthanased 0.5, 1, 2, 6, 24, 48 h after trauma. Brain tissue samples were taken 5 mm away from the left frontal pole and also from the corresponding point of the contralateral hemispheres. Malondialdehyde activity (MDA) was considered to reflect the degree of lipid peroxidation. The MDA levels continued to increase for the first 2 h after the injury, then started to decrease gradually. Memantine treatment significantly reduced lipid peroxidation levels in the treatment group compared with other groups (P<0.01). The findings of the present study indicate that memantine provides beneficial effects after closed head trauma in rats.
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PMID:The effects of memantine on lipid peroxidation following closed-head trauma in rats. 1578 51