BACKGROUND AND OBJECTIVES: Tinnitus is one of the most widespread disorders of the auditory system, affecting approximately 17% of the general population, with the frequency increasing to about 33% in the elderly. However, little is known about the underlying physiological mechanism that causes tinnitus and there is no definite treatment. Recently, several studies have showed that subjective tinnitus is mostly generated at the synapse between inner hair cells and their afferent nerves and in addition, some have showed that glutamate is likely to act as the neurotransmitter. The aim of this study has been to evaluate the effective use of caroverine hydrochloride and memantine hydrochloride for tinnitus treatment and to determine their appropriate indication of glutamate antagonist therapy. MATERIALS AND METHOD: From May 1998 through June 2000, 188 patients with subjective tinnitus were treated with caroverine hydrochloride (Spamon(R)). Of the patients, 153 were followed, and 20 of these patients who did not respond to caroverine hydrochloride were treated additionally with memantine hydrochloride (Akatinol(R)). Audiological evaluations were performed in all of the patients. Pre and post-treatment status was analyzed by handicap inventories. RESULTS: Subjective tinnitus was improved in 55 (35.9%) of 153 patients who were treated with caroverine hydrochloride and 11 (55.0%) of 20 patients with memantine hydrochloride. The response group had tendency of shorter duration history of tinnitus than the non-response group. There was no difference between the response group and the non-response group in age, sex, site, and tinnitus characteristics. CONCLUSION: We suggest that glutamate antagonists such as caroverine hydrochloride and memantine hydrochloride can be used as an alternative modality for treatment of subjective tinnitus.
Aged ; Equipment and Supplies ; Excitatory Amino Acid Antagonists ; Glutamic Acid* ; Hair ; Humans ; Memantine ; Neurotransmitter Agents ; Synapses ; Tinnitus*

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism

AIMTo study the protective effects and the mechanisms of sevoflurane on ischemic cerebral neurons.

METHODSWith electrophysiological microelectrode recoding technique, the OPS of hippocampal slices deprived with oxygen and glucose (OGD) and injured from toxicity of glutamate (Glu) in the control group, 2% sevoflurane group and 4% sevoflurane group were observed. The changes of ultrastructure in the three groups were also observed respectively.

RESULTSIn the control group and 2% sevoflurane group it didn't show the improvement of recovery in OPS of hippocampal slices injured from OGD and Glu. In 4% sevoflurane group the recovery degree and the recovery rate of OPS were obversely. With electricmicroscope, it was founded that in the control group and 2% sevoflurane group, the pyramidal neurons in CA1 regions deprived with glucose and oxygen and exposured by Glu were damaged. Intercellular edema were severe, the nucleus membranes were not complete, the chromatin formed mass, the endoplasmic reticulum in the cytoplasm were degenerate, mitochondrion swelled. In 4% sevoflurane group, the pyramidal neurons in CA1 regions did not swell obviously, the nucleus was clear, the nucleus membranes were complete and the mitochondria swelled lightly.

CONCLUSION4% sevoflurane could protect hippocampal neurons deprived with glucose and oxygen from the damage. The probable mechanism is 4% sevoflurane reduced the excitatory of Glu.

Anesthetics, Inhalation ; pharmacology ; Animals ; Brain Ischemia ; physiopathology ; Excitatory Amino Acid Antagonists ; pharmacology ; Hippocampus ; blood supply ; In Vitro Techniques ; Male ; Methyl Ethers ; pharmacology ; Neuroprotective Agents ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; prevention & control

The purpose of this study was to evaluate the neuroprotective effect of memantine, a N-methyl-D-aspartate antagonist, in an experimental optic nerve ischemia. Endothelin-1 (ET-1) in a dosage of 0.1 microg/day was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for 8 weeks in 10 rabbits. In 5 rabbits, 1 mg/kg memantine was administered concurrently by intramuscular injection once a daily. Morphologic optic nerve head changes were monitored with a confocal scanning laser ophthalmoscope. Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth and rim volume), indicating an increase in optic nerve head cupping and a decrease of neural rim volume in the ET-1 administered eyes (P < 0.0001). In rabbits where memantine was given concurrently with ET-1, no significant change in topometric parameters was observed after ET-1 administration (P = 0.78). The current results suggest that memantine has a neuroprotective effect in optic nerve ischemia. Memantine may potentially be useful in the management of various ischemic disorders of the optic nerve, including glaucoma.
Animal ; Comparative Study ; Endothelin-1/toxicity ; Excitatory Amino Acid Antagonists/*therapeutic use ; Male ; Memantine/*therapeutic use ; Models, Animal ; Neuroprotective Agents/*therapeutic use ; Optic Disk/*drug effects/pathology ; Optic Nerve/*drug effects/pathology ; Optic Neuropathy, Ischemic/chemically induced/pathology/*prevention & control ; Rabbits

We evaluated the efficacy of non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) as an adjuvant therapy in experimental neonal bacterial meningitis. Meningitis was induced by injecting 10(6) colony forming units of Escherichia coli into the cisterna magna. MK-801 3 mg/kg was given as a bolus intravenous injection, 30 min before the induction of meningitis. MK-801 did not down-modulate the inflammatory parameters, such as increased intracranial pressure, cerebrospinal fluid (CSF) leukocytosis, increased lactate and TNF-alpha levels in the CSF, and hypoglycorrhachia observed in the meningitis group. MK-801 did not significantly attenuate the elevated glutamate concentration in the CSF. However, MK-801 showed some neuroprotective effects as evidenced by significant attenuation of cerebral lipid peroxidation products (conjugated dienes) and increase of brain high-energy phosphate compounds (ATP and PCr). Improvement in cerebral cortical cell membrane Na+, K+ -ATPase activity did not reach a statistical significance. These results suggest that MK-801 was effective in ameliorating brain injury in neonatal bacterial meningitis, although it failed to attenuate the inflammatory responses.
Animals ; Animals, Newborn ; Blood Glucose/metabolism ; Brain/cytology ; Brain/drug effects* ; Brain/metabolism ; Cell Membrane/drug effects* ; Cell Membrane/metabolism ; Cerebral Cortex/metabolism ; Dizocilpine Maleate/pharmacology* ; Energy Metabolism* ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/cerebrospinal fluid ; Lactic Acid/blood ; Leukocytes/metabolism ; Meningitis, Escherichia coli/drug therapy ; Meningitis, Escherichia coli/metabolism* ; Neurons/drug effects* ; Neurons/metabolism ; Neuroprotective Agents/pharmacology* ; Random Allocation ; Swine ; Tumor Necrosis Factor/cerebrospinal fluid

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.
Animals ; Brain ; drug effects ; metabolism ; pathology ; Cognitive Dysfunction ; drug therapy ; metabolism ; pathology ; Disease Models, Animal ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Hydrocarbons, Brominated ; Inflammasomes ; drug effects ; metabolism ; Male ; Maze Learning ; drug effects ; physiology ; Microglia ; drug effects ; metabolism ; pathology ; NLR Family, Pyrin Domain-Containing 3 Protein ; metabolism ; Neurons ; drug effects ; metabolism ; pathology ; Nootropic Agents ; pharmacology ; Random Allocation ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; metabolism ; Spatial Memory ; drug effects ; physiology ; Specific Pathogen-Free Organisms

Estrogen replacement therapy in postmenopausal women may reduce the risk of Alzheimer's disease, possibly by ameliorating neuronal degeneration. In the present study, we examined the neuroprotective spectrum of estrogen against excitotoxicity, oxidative stress, and serum-deprivation-induced apoptosis of neurons in mouse cortical cultures. 17beta-estradiol as well as 17alpha-estradiol and estrone attenuated oxidative neuronal death induced by 24 hr exposure to 100 microM FeCl2, excitotoxic neuronal death induced by 24 hr of exposure to 30 microM N-methyl-D-aspartate (NMDA) and serum-deprivation induced neuronal apoptosis. Furthermore, estradiol attenuated neuronal death induced by Abeta25-35. However, all these neuroprotective effects were mediated by the anti-oxidative action of estrogens. When oxidative stress was blocked by an antioxidant trolox, estrogens did not show any additional protection. Addition of a specific estrogen receptor antagonist ICI182,780 did not reverse the protection offered by estrogens. These findings suggest that high concentrations of estrogen protect against various neuronal injuries mainly by its anti-oxidative effects as previously shown by Behl et al. Our results do not support the view that classical estrogen receptors mediate neuroprotection.
Amyloid beta-Protein/pharmacology ; Animal ; Antioxidants/pharmacology* ; Antioxidants/metabolism ; Apoptosis/drug effects* ; Cells, Cultured ; Chelating Agents/pharmacology ; Chromans/pharmacology ; Estradiol/pharmacology ; Estrogens/pharmacology* ; Estrogens/metabolism ; Estrone/pharmacology ; Ethylenediamines/pharmacology ; Excitatory Amino Acid Agonists/pharmacology ; Ferric Compounds/pharmacology ; Lactate Dehydrogenase/analysis ; Mice ; N-Methylaspartate/pharmacology ; Neurons/metabolism ; Neurons/drug effects* ; Neurons/cytology ; Organ of Corti/cytology ; Peptide Fragments/pharmacology ; Staurosporine/pharmacology

Estrogen replacement therapy in postmenopausal women may reduce the risk of Alzheimer's disease, possibly by ameliorating neuronal degeneration. In the present study, we examined the neuroprotective spectrum of estrogen against excitotoxicity, oxidative stress, and serum-deprivation-induced apoptosis of neurons in mouse cortical cultures. 17beta-estradiol as well as 17alpha-estradiol and estrone attenuated oxidative neuronal death induced by 24 hr exposure to 100 microM FeCl2, excitotoxic neuronal death induced by 24 hr of exposure to 30 microM N-methyl-D-aspartate (NMDA) and serum-deprivation induced neuronal apoptosis. Furthermore, estradiol attenuated neuronal death induced by Abeta25-35. However, all these neuroprotective effects were mediated by the anti-oxidative action of estrogens. When oxidative stress was blocked by an antioxidant trolox, estrogens did not show any additional protection. Addition of a specific estrogen receptor antagonist ICI182,780 did not reverse the protection offered by estrogens. These findings suggest that high concentrations of estrogen protect against various neuronal injuries mainly by its anti-oxidative effects as previously shown by Behl et al. Our results do not support the view that classical estrogen receptors mediate neuroprotection.
Amyloid beta-Protein/pharmacology ; Animal ; Antioxidants/pharmacology* ; Antioxidants/metabolism ; Apoptosis/drug effects* ; Cells, Cultured ; Chelating Agents/pharmacology ; Chromans/pharmacology ; Estradiol/pharmacology ; Estrogens/pharmacology* ; Estrogens/metabolism ; Estrone/pharmacology ; Ethylenediamines/pharmacology ; Excitatory Amino Acid Agonists/pharmacology ; Ferric Compounds/pharmacology ; Lactate Dehydrogenase/analysis ; Mice ; N-Methylaspartate/pharmacology ; Neurons/metabolism ; Neurons/drug effects* ; Neurons/cytology ; Organ of Corti/cytology ; Peptide Fragments/pharmacology ; Staurosporine/pharmacology

BACKGROUNDS: The importance of toxic extracellular levels of excitatory amino acids, as well as of high extracellular levels of inhibitory amino acids, is considered to be related with the pathophysiology of neuronal cell loss during cerebral ischemia. METHODS: The extracellular concentration of glutamate, glycine, and taurine in the hippocampus were determined during and after transient global ischemia in the New Zealand white rabbit. Because the cerebroprotective effects of profound hypothermia are well known and clinically widely used,we used the hypothermia group as an experimental group compared with normothermic control group in the experimental protocol. To derive a quantitative descriptor reflecting the magnitude of amino acid neurotransmitter changes with ischemia, we defined the 'taurine index' as: [glutamate]x[glycine]/[taurine]. RESULTS: Ischemia led to large increases in both excitatory (glutamate and glycine) and inhibitory amino acids(taurine) in the normothermic group. Taurine index was increased during ischemia and after reperfusion and had a close relationship with the severity of ischemia-induced neuronal damage. CONCLUSIONS: The taurine index appears to be a reliable biochemical marker to determine the severity of ischemic injury.
Amino Acids ; Biomarkers ; Brain Ischemia ; Excitatory Amino Acids ; Glutamic Acid ; Glycine ; Hippocampus ; Hypothermia ; Ischemia ; Neurons ; Neurotransmitter Agents ; New Zealand ; Reperfusion ; Subject Headings ; Taurine*

Memantine and other glutamatergic agents have been currently investigated in some off-label indications due to glutamatergic involvement in several psychoneurological disorders. We assumed that memantine similarly to ketamine may positively influence mood, moreover having a potential to improve cognition and general quality of life. We report a case of a 49-year-old male hospitalized during a manic and a subsequent moderate depressive episode. After an ineffective use of lithium, olanzapine and antidepressive treatment with mianserin, memantine was added up to 20 mg per day for 10 weeks. The mental state was assessed using the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Inventory, the World Health Organization Quality of Life Scale and psychological tests. After 10 weeks the patient achieved a partial symptomatic improvement in mood, anxiety and quality of sleep, but his activity remained insufficient. We also observed an improvement in the parameters of cognitive functioning and quality of life. There was neither significant mood variations during the memantine use nor mood changes after its termination. No significant side effects were noted during the memantine treatment. We conclude that using memantine in bipolar depression may improve mood, cognitive functioning and quality of life.
Anxiety ; Bipolar Disorder* ; Cognition ; Depression ; Excitatory Amino Acid Agents ; Glutamic Acid ; Humans ; Ketamine ; Lithium ; Male ; Memantine* ; Mianserin ; Middle Aged ; Psychological Tests ; Quality of Life* ; World Health Organization