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*

To examine the protection of retinal cell death by glutamate antagonists in vivo, this study was carried out in pressure-induced ischemia model. Firstly, we observed that ischemia resulted in the similar retinaldamage to the injuries caused by NMAD and Kainate toxicity. Secondly, the retinal cell death caused by ischemia was prevented by MK801 and CNQX, glutamate antagonists for NMDA and Kainate excitotoxicity, respectively at 24hr after ischemia. MK801 was shown to prevent the cell death in ganglion cell layer and CNQX in inner unclear layer. In addition, the combination of CNQX and MK801 protected the retina neuronal cell from ischemic injury better than when they were applied separately. The partial protection of retinal cell death by glutamate antagonists in ischemia model indicates that glutamate eoxicity as well as other cell death mechanism such as apoptosis mediates ischemia induced retinal cell death. Thus, cell death by other mechanism must be also blocked in order to prevent retinal cell death, completely.
6-Cyano-7-nitroquinoxaline-2,3-dione* ; Apoptosis ; Cell Death ; Dizocilpine Maleate* ; Excitatory Amino Acid Antagonists ; Ganglion Cysts ; Glutamic Acid ; Ischemia* ; Kainic Acid* ; N-Methylaspartate* ; Neurons ; Retina ; Retinaldehyde*

OBJECTIVETo study the changes of excitatory amino acids (EAAs) and intracellular calcium ([Ca2+]i), and the protective effect of EAAs receptor antagonists in the tissues of rabbit lumbar spinal cord after 40-minues ischemia and 4-hours reperfusion.

METHODSThirty healthy rabbits were divided into six groups: sham-operation, 40-minues ischemia, 4-hour reperfusion, ketamine and MgSO4 treatment, ketamine treatment, and saline treatment groups. The contents of EAAs (glutamate and aspartate) and [Ca2+]i were measured.

RESULTSThe contents of glutamate and aspartate were decreased to 15.18 micromol/g+/-2.33 micromol/g and 9.99 micromol/g+/-0.69 micromol/g, respectively; 13.75 micromol/g+/-2.58 micromol/g and 6.49 micromol/g+/-1.39 micromol/g after reperfusion. In the ischemia group, the [Ca2+]i was elevated to 221.2 microg/g+/-4.27 microg/g, and elevated further to 298.3 microg/g+/-9.26 microg/g after reperfusion, being significantly higher than that of ischemia and control groups. Ketamine could obviously increase the level of glutamate and aspartate and decrease the level of [Ca2+]i during the ischemia and reperfusion injury.

CONCLUSIONSThe excitotoxicity of EAAs and the overload of calcium induced by EAAs play a harmful role in ischemia and reperfusion injury. Ketamine has an effective inhibitory effect.

Animals ; Calcium ; analysis ; Excitatory Amino Acids ; blood ; Female ; Ischemia ; blood ; Male ; Rabbits ; Random Allocation ; Receptors, Amino Acid ; antagonists & inhibitors ; Reperfusion Injury ; blood ; Spinal Cord ; blood supply

Animals ; Brain Ischemia ; complications ; physiopathology ; Excitatory Amino Acid Antagonists ; pharmacology ; Humans ; Infant, Newborn ; Leukomalacia, Periventricular ; etiology ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; physiology ; Signal Transduction ; physiology

Significant evidence supports the role of the vestibular system in the regulation of blood pressure during postural movements. In the present study, the role of the vestibulo-spino-adrenal (VSA) axis in the modulation of blood pressure via the vestibulosympathetic reflex was clarified by immunohistochemical and enzyme immunoassay methods in conscious rats with sinoaortic denervation. Expression of c-Fos protein in the intermediolateral cell column of the middle thoracic spinal regions and blood epinephrine levels were investigated, following microinjection of glutamate receptor agonists or antagonists into the medial vestibular nucleus (MVN) and/or sodium nitroprusside (SNP)-induced hypotension. Both microinjection of glutamate receptor agonists (NMDA and AMPA) into the MVN or rostral ventrolateral medullary nucleus (RVLM) and SNP-induced hypotension led to increased number of c-Fos positive neurons in the intermediolateral cell column of the middle thoracic spinal regions and increased blood epinephrine levels. Pretreatment with microinjection of glutamate receptor antagonists (MK-801 and CNQX) into the MVN or RVLM prevented the increased number of c-Fos positive neurons resulting from SNP-induced hypotension, and reversed the increased blood epinephrine levels. These results indicate that the VSA axis may be a key component of the pathway used by the vestibulosympathetic reflex to maintain blood pressure during postural movements.
Animals ; Axis, Cervical Vertebra* ; Blood Pressure* ; Denervation ; Epinephrine ; Excitatory Amino Acid Antagonists ; Glutamic Acid ; Hypotension ; Immunoenzyme Techniques ; Microinjections ; Neurons ; Nitroprusside ; Rats* ; Receptors, Glutamate ; Reflex* ; Vestibular Nuclei ; Natural Resources

Retinal neurons are highly vulnerable to hypoxia/ischemia. Excitotoxicity and free radical injury have been proposed as the major mechanisms of ischemic retinal injury have been proposed as the major mechanisms of ischemic retinal neuronal death. In the present study, we examined these possibilities in retinal cultures. Exposure of these cultures to hypoxia for 48 hr induced selective death of neurons. Addition of an antioxidiant trolox markedly attenuated hypoxiainduced retinal neuronal death, whereas addition of glutamate antagonists, MK-801 or CNQX,did not. Morphologically, hypoxic neuronal death in cultures was accompanied by cell body swelling, a feature of necrosis, yet simultaneously exhibited some features of apoptosis such as TUNEL positivity and protection by cycloheximide. However, unlike in classical programmed cell death, adding buthionine sulfoximine, a potent inhibitor of glutathione synthesis, completely reversed the protective effect of cycloheximide. The results have demonstrated that free radical injury is the main mechanism of neuronal death in the present retinal culture, and suggest an intriguing possibility that free redical injury may become a prominent mechanism, when excitotoxic injury is masked.
Animals ; Anoxia ; Apoptosis ; Buthionine Sulfoximine ; Cell Death ; Cycloheximide ; Dizocilpine Maleate ; Excitatory Amino Acid Antagonists ; Glutathione ; In Situ Nick-End Labeling ; Masks ; Necrosis ; Neurons ; Rats* ; Retinal Neurons* ; Retinaldehyde*

BACKGROUND: Previous reports have described NMDA antagonist reduced the nerve injury induced or inflammatory thermal hyperalgesia. This study evaluated the effects of spinally administered excitatory amino acid antagonists on the thermal hyperalgesia state induced by mild burn. METHODS: The measured response was the latency to paw withdrawal of each hindpaw after application of a focused heat lamp on the plantar surface of the paw through a glass plate upon which the animal stood. In this work, MK801, non-competitive NMDA receptor antagonist, AP5, competitive NMDA receptor antagonist, CNQX, non-NMDA receptor antagonist were injected through chronically implanted lumbar intrathecal catheters in rats with mild burn injury on the right hindpaw. RESULTS: In the normal left hindpaw, MK801, AP5 and CNQX had little effect upon paw withdrawal latency (PWL) at intrathecal doses which do not produce readily detectable motor weakness. In the right hyperalgesic hindpaw, AP5 significantly reduced PWL at a dose-dependent fashion, MK801 reduced PWL to some extent, and CNQX did not reduced PWL. CONCLUSIONS: These results suggested that spinal NMDA receptors play an important role in the hyperalgesia induced by mild burn injury.
6-Cyano-7-nitroquinoxaline-2,3-dione ; Animals ; Burns ; Catheters ; Dizocilpine Maleate ; Excitatory Amino Acid Antagonists ; Glass ; Hot Temperature ; Hyperalgesia* ; N-Methylaspartate* ; Rats* ; Receptors, N-Methyl-D-Aspartate

AIMTo investigate the possible involvement of glutamate(Glu) in the paraventricular nucleus (PVN) in the central regulation of baroreflex.

METHODSThe baroreflex was induced by intravenous injection of phenylephrine in conscious rats, and the extracellular concentration of Glu in the PVN region was measured by microdialysis and high performance liquid chromatography (HPLC) techniques. To determine whether the observed Glu release was involved in the baroreflex, NMDA and non-NMDA receptor antagonists, MK-801 and CNQX, were perfused in the PVN region during baroreflex.

RESULTSDuring baroreflex, the Glu concentration in the PVN region immediately increased to 384.82% +/- 91.77% of basal level (P < 0.01). (2) During baroreflex, direct perfusion of MK-801 and CNQX in the PVN were attenuated the increase of blood pressure and enhanced the decrease of HR (P < 0.01),resulting a significant increase in baroreflex sensitivity (P < 0.01).

CONCLUSIONGlutamate in PVN is involved in central regulation of baroreflex, which may inhibit baroreflex via ionothopic glutamate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione ; pharmacology ; Animals ; Baroreflex ; drug effects ; physiology ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Male ; Paraventricular Hypothalamic Nucleus ; physiology ; Rats ; Rats, Wistar

OBJECTIVEThe present study was undertaken to design antisense oligodeoxynucleotides (AS-ODNs) of glial glutamate transporter-la (GLT-1a) and to evaluate the effectiveness of the designed AS-ODNs on the expression of GLT-1a.

METHODSFive sequences of GLT-1a AS-ODNs were designed according to the C terminus specific sequences of GLT-1a mRNA using antisense design software of IDT Com- pany. Western blot analysis was used to evaluate the inhibition effects of the five GLT-1a AS-ODNs on the expression of GLT-la.

RESULTSThe sequence of GLT-1a AS-ODNs with sequence of 5'-GGTTCTTCCTCAACACTGCA-3' could specifically inhibit the expression of GLT-1a in the hippocampal CA1 subfield of rats, while it had no effect on the expression of GLT-1b. This sequence showed similar inhibition on the expression of GLT-la in sham and ceftriaxone (Cef)-treated rats. It could also significantly inhibit the cerebral ischemic preconditioning (CIP)-induced up-regulation in the expression of GLT-1a. The magnitude of the inhibition in sham, Cef- or CIP-treated rats was similar by more than 60%.

CONCLUSIONFrom the designed five sequences of GLT-1a AS-ODNs, we obtained an effective sequence which can specifically inhibit the expression of GLT-1a.

Animals ; CA1 Region, Hippocampal ; metabolism ; Excitatory Amino Acid Transporter 2 ; antagonists & inhibitors ; metabolism ; Ischemic Preconditioning ; Oligonucleotides, Antisense ; genetics ; RNA, Messenger ; Rats ; Up-Regulation

OBJECTIVETo investigate the role of N-Methyl-D-aspartic acid (NMDA)-type glutamate receptors in the central nucleus of the amygdale (CeA) in food and water intake.

METHODSMale Sprague-Dawley rats with stainless steel cannulae implanted unilaterally into the CeA were used. The prototypic NMDA receptor agonist NMDA, or the selective NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) was microinjected into the CeA of satiated and euhydrated rats.

RESULTSIntra-CeA injection of 8.50, 17.00, or 34.00 nmol NMDA did not alter food intake but significantly increased water intake 0-1 h after the injection (F(3,32)=3.191, P=0.037) independent of food intake. Without affecting the food intake, injection of 6.34, 12.70, or 25.40 nmol D-AP-5 into the CeA significantly decreased water intake 0-1 h after the injection (F(3,28)=3.118, P=0.042) independent of food intake.

CONCLUSIONNMDA receptors in the CeA may participate in the control of water intake rather than food intake.

2-Amino-5-phosphonovalerate ; pharmacology ; Amygdala ; drug effects ; Animals ; Drinking ; drug effects ; Eating ; drug effects ; Excitatory Amino Acid Agonists ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Injections, Intraventricular ; Male ; N-Methylaspartate ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; agonists ; antagonists & inhibitors