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Biomedical subjects

V L Rao

Publications and source records attributed to V L Rao.

At least 19 recordsLinked to original sources
PubMed2001

Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats.

This study investigated whether memantine, a non-competitive NMDA receptor antagonist is neuroprotective after traumatic brain injury (TBI) induced in adult rats with a controlled cortical impact device. TBI led to significant neuronal death in the hippocampal CA2 and CA3 regions (by 50 and 59%, respectively), by 7 days after the injury. Treatment of rats with memantine (10 and 20 mg/Kg, i.p.) immediately after the injury significantly prevented the neuronal loss in both CA2 and CA3 regions. This is the first study showing the neuroprotective potential of memantine to prevent the TBI-induced neuronal damage.

Animals↗
PubMed2001

Up-regulation of the peripheral-type benzodiazepine receptor expression and [(3)H]PK11195 binding in gerbil hippocampus after transient forebrain ischemia.

In mammalian CNS, the peripheral-type benzodiazepine receptor (PTBR) is localized on the outer mitochondrial membrane within the astrocytes and microglia. The main function of PTBR is to transport cholesterol across the mitochondrial membrane to the site of neurosteroid biosynthesis. The present study evaluated the changes in the PTBR density, gene expression and immunoreactivity in gerbil hippocampus as a function of reperfusion time after transient forebrain ischemia. Between 3 to 7 days of reperfusion, there was a significant increase in the maximal binding site density (B(max)) of the PTBR antagonist [(3)H]PK11195 (by 94-156%; P < 0.01) and PTBR mRNA levels (by 1.8- to 2.9-fold; P < 0.01). At 7 days of reperfusion, in the hippocampal CA1 (the brain region manifesting selective neuronal death), PTBR immunoreactivity increased significantly. Increased PTBR expression after transient forebrain ischemia may lead to increased neurosteroid biosynthesis, and thus may play a role in the ischemic pathophysiology.

Animals↗
PubMed2001

Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain.

Transient focal cerebral ischemia leads to extensive neuronal damage in cerebral cortex and striatum. Normal functioning of glutamate transporters clears the synaptically released glutamate to prevent excitotoxic neuronal death. This study evaluated the functional role of the glial (GLT-1) and neuronal (EAAC1) glutamate transporters in mediating ischemic neuronal damage after transient middle cerebral artery occlusion (MCAO). Transient MCAO in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) led to increased infarct volume (45 +/- 8%; p < 0.05), worsened neurological status, and increased mortality rate, compared with GLT-1 sense/random ODN-infused controls. Transient MCAO in rats infused with EAAC1 antisense ODNs had no significant effect on any of these parameters. This study suggests that GLT-1, but not EAAC1, knockdown exacerbates the neuronal death and thus neurological deficit after stroke.

ATP-Binding Cassette Transporters↗
PubMed2001

Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain.

Transient focal cerebral ischemia leads to extensive excitotoxic neuronal damage in rat cerebral cortex. Efficient reuptake of the released glutamate is essential for preventing glutamate receptor over-stimulation and neuronal death. Present study evaluated the expression of the glial (GLT-1 and GLAST) and neuronal (EAAC1) subtypes of glutamate transporters after transient middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. Between 24h to 72h of reperfusion after transient MCAO, GLT-1 and EAAC1 protein levels decreased significantly (by 36% to 56%, p < 0.05) in the ipsilateral cortex compared with the contralateral cortex or sham control. GLT-1 and EAAC1 mRNA expression also decreased in the ipsilateral cortex of ischemic rats at both 24h and 72h of reperfusion, compared with the contralateral cortex or sham control. Glutamate transporter down-regulation may disrupt the normal clearance of the synaptically-released glutamate and may contribute to the ischemic neuronal death.

Amino Acid Transport System X-AG↗
PubMed2001

GeneChip analysis after acute spinal cord injury in rat.

Spinal cord injury (SCI) leads to induction and/or suppression of several genes, the interplay of which governs the neuronal death and subsequent loss of motor function. Using GeneChip, the present study analyzed changes in the mRNA abundance at 3 and 24 h after SCI in adult rats. SCI was induced at T9 level by the New York University impactor by dropping a 10-g weight from a height of 25 mm. Several transcription factors, immediate early genes, heat-shock proteins, pro-inflammatory genes were up-regulated by 3 h, and persisted at 24 h, after SCI. On the other hand, some neurotransmitter receptors and transporters, ion channels, kinases and structural proteins were down-regulated by 3 h, and persisted at 24 h, after SCI. Several genes that play a role in growth/differentiation, survival and neuroprotection were up-regulated at 24 h after SCI. Using real-time quantitative PCR, the changes observed by GeneChip were confirmed for seven up-regulated (interleukin-6, heat-shock protein-70, heme oxygenase-1, suppressor of cytokine signaling 2, suppressor of cytokine signaling 3, interferon regulatory factor-1, neuropeptide Y), two down-regulated (vesicular GABA transporter and cholecystokinin precursor) and two unchanged (Cu/Zn-superoxide dismutase and phosphatidyl inositol-3-kinase) genes. The present study shows that inflammation, neurotransmitter dysfunction, increased transcription, ionic imbalance and cytoskeletal damage starts as early as 3 h after SCI. In addition to these effects, 24 h after SCI the repair and regeneration process begins in an attempt to stabilize the injured spinal cord.

Acute Disease↗
PubMed2001

Protective effects of glial cell line-derived neurotrophic factor on hippocampal neurons after traumatic brain injury in rats.

OBJECT: The purpose of this study was to evaluate whether glial cell line-derived neurotrophic factor (GDNF) can protect against hippocampal neuronal death after traumatic brain injury (TBI). METHODS: Male Sprague-Dawley rats were subjected to moderate TBI with a controlled cortical impact device while in a state of halothane-induced anesthesia. Then, GDNF or artificial cerebrospinal fluid ([aCSF]; vehicle) was infused into the frontal horn of the left lateral ventricle. In eight brain-injured and eight sham-operated rats, GDNF was infused continuously for 7 days (200 ng/day intracerebroventricularly at a rate of 8.35 ng/0.5 microl/hour). An equal volume of vehicle was infused at the same rate into the remaining eight brain-injured and eight sham-operated rats. Seven days post-injury, all rats were killed. Their brains were sectioned and stained with cresyl violet, and the hippocampal neuronal loss was evaluated in the CA2 and CA3 regions with the aid of microscopy. A parallel set of sections from each brain was subjected to immunoreaction with antibodies against glial fibrillary acidic protein (GFAP; astroglia marker). In the aCSF-treated group, TBI resulted in a significant neuronal loss in the CA2 (60%, p < 0.05) and CA3 regions (68%, p < 0.05) compared with the sham-operated control animals. Compared with control rats infused with aCSF, GDNF infusion significantly decreased the TBI-induced neuronal loss in both the CA2 (58%, p < 0.05) and CA3 regions (51%, p < 0.05). There was no difference in the number of GFAP-positive astroglial cells in the GDNF-infused rats in the TBI and sham-operated groups compared with the respective vehicle-treated groups. CONCLUSIONS: The authors found that GDNF treatment following TBI is neuroprotective.

Animals↗
PubMed2001

Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain.

Traumatic injury to rat brain induced by controlled cortical impact (CCI) results in chronic neuronal death in the hippocampus. In the normal brain, glutamate transporters actively clear the glutamate released synaptically to prevent receptor overactivation and excitotoxicity. Glutamate transporter 1 (GLT-1) is the most abundant and active glutamate transporter, which mediates the bulk of glutamate uptake. CCI injury significantly decreased GLT-1 mRNA (by 49-66%, P < 0.05) and protein (by 29-44%, P < 0.05) levels in the ipsilateral hippocampus, compared with either the respective contralateral hippocampus or the sham-operated control, 24-72 h after the injury. CCI injury in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) exacerbated the hippocampal neuronal death and mortality, compared with the GLT-1 sense/random ODN-infused controls. At 7 days after the injury, hippocampal neuronal numbers were significantly lower in the CA1 (reduced by 32%, P < 0.05), CA2 (by 45%, P < 0.01), CA3 (by 68%, P < 0.01) and dentate gyrus (by 31%, P < 0.05) in GLT-1 antisense ODN-infused rats, compared with the GLT-1 sense/random ODN-infused controls. This study suggested a role for GLT-1 dysfunction in promoting the hippocampal neuronal death after traumatic brain injury.

ATP-Binding Cassette Transporters↗
PubMed2000

Five diterpenoids (agallochins A-E) from the mangrove plant Excoecaria agallocha Linn.

Chemical examination of the hexane extract of the roots of Excoecaria agallocha Linn collected from the Godavari estuary resulted in the isolation of altogether eleven diterpenoids of which five (1-5) are new. The structures of the new diterpenoids have been elucidated by a study of their physical and spectral (UV, IR, 1H, 13C, DEPT, 1H-1H COSY, NOESY, HMQC, HMBC and MASS) data as 3-oxo-ent-13epi-8(13)-epoxy-15-chloro-14-hydroxylabdane (1), ent-15-chloro-13,14-dihydroxylabd-8(9)-en-3-one (2), ent-15-chloro-labd-8(9)ene-3alpha,13,14-triol (3), ent-11beta-hydroxy-8(14),15-isopimaradien-3-one (4), 8,13-epoxy-3-nor-2,3-seco-14-epilabden-2,4-olide (5). The six known diterpenoids have been characterised respectively as ent-3-oxo-13-epi-manoyl oxide (6), ent-3beta-hydroxy-13-epi-manoyl oxide (7), (13R,14S)-ent-8alpha,13;14,15-diepoxy-13-epi-labdan-3-one (8), ent-16-hydroxy-3-oxo-13-epimanoyl oxide (9), ent-15-hydroxylabda-8(17),13E-dien-3-one (10), labda-8(17),13E-diene-3beta,15-diol (11) by a comparative study of their spectral data with the literature values.

Diterpenes↗
PubMed1999

Protective effects of memantine against ischemia-reperfusion injury in spontaneously hypertensive rats.

Memantine, an uncompetitive NMDA open-channel blocker, has been shown to be effective in preventing neuronal damage after permanent focal cerebral ischemia. Reperfusion after a long period of ischemia may aggravate the progression of neuronal damage. Those drugs that show protective effects after permanent cerebral ischemia, therefore, might fail to do so against ischemia-reperfusion injury. In this study we evaluated the effects of memantine on brain edema formation and ischemic injury volume after transient cerebral ischemia. Male Spontaneously Hypertensive Rats (SHR) weighing 250-300 g were anesthetized with halothane and subjected to 1 hour of temporary middle cerebral artery occlusion by an intraluminal suture. 20 mg/kg of memantine or saline were injected intraperitoneally 5 min. after the induction of ischemia. Physiological parameters and regional cerebral blood flow were monitored during the surgical procedure. Brain water content and ischemic injury volume were measured with the wet dry method and 2,3,5-triphenyl tetrazolium chloride monohydrate (TTC) staining, respectively, at 24 hours after occlusion. There were no statistically significant differences between the groups regarding physiological parameters during the procedure. Memantine treatment (n=9) reduced the brain water content significantly in the cortex compared to saline treatment (n=8; 83. 1+/-0.7% vs. 84.5+/-1.5%, respectively, p<0.05). The total volume of ischemic brain injury was 300+/-49 mm(3) in the animals treated with saline (n=13). Treatment with 20 mg/kg memantine (n=14) reduced the ischemic injury volume to 233+/-61 mm(3) (P<0.01). These results demonstrate that the harmful effects of recirculation after a period of ischemia can be attenuated by the treatment of memantine, perhaps by its action at the NMDA receptors.

Animals↗
PubMed1999

Portacaval anastomosis causes selective alterations of peripheral-type benzodiazepine receptor expression in rat brain and peripheral tissues.

There is a growing body of evidence to suggest that peripheral-type benzodiazepine receptors (PTBRs) and their endogenous ligands are implicated in the pathogenesis of end-organ failure in chronic liver disease. Portal-systemic encephalopathy, a major neuropsychiatric complication associated with chronic liver disease, results in activation of brain PTBR and probably in peripheral organs. In order to address these issues, PTBR mRNA was measured using semi-quantitative RT-PCR in extracts of cerebral cortex, kidney and testis of rats four weeks after end-to-side portacaval anastomosis and sham-operation (controls). Densities of PTBR sites were measured concomitantly by in vitro receptor binding using the selective PTBR ligand [3H]PK11195. Portacaval shunting resulted in a 2 to 3-fold increase in expression of PTBR in brain and kidney and a 37% reduction in expression in testis. Densities of [3H]PK11195 sites changed in parallel with the alterations of gene expression. These findings suggest that selective alterations of PTBR expression are implicated in the pathogenesis of peripheral tissue hypertrophy (kidney) and/or atrophy (testis) which accompanies portal-systemic shunting in chronic liver failure. In brain, activation of PTBR could result in an increase in the production of neurosteroids with potent inhibitory action in the CNS, which could contribute to the pathogenesis of portal-systemic encephalopathy.

Animals↗
PubMed1999

Effects of MDL 72527, a specific inhibitor of polyamine oxidase, on brain edema, ischemic injury volume, and tissue polyamine levels in rats after temporary middle cerebral artery occlusion.

The possible effects of the polyamine interconversion pathway on tissue polyamine levels, brain edema formation, and ischemic injury volume were studied by using a selective irreversible inhibitor, MDL 72527, of the interconversion pathway enzyme, polyamine oxidase. In an intraluminal suture occlusion model of middle cerebral artery in spontaneously hypertensive rats, 100 mg/kg MDL 72527 changed the brain edema formation from 85.7 +/- 0.3 to 84.5 +/- 0.9% in cortex (p < 0.05) and from 79.9 +/- 1.7 to 78.4 +/- 2.0% in subcortex (difference not significant). Ischemic injury volume was reduced by 22% in the cortex (p < 0.05) and 17% in the subcortex (p < 0.05) after inhibition of polyamine oxidase by MDL 72527. There was an increase in tissue putrescine levels together with a decrease in spermine and spermidine levels at the ischemic site compared with the nonischemic site after ischemia-reperfusion injury. The increase in putrescine levels at the ischemic cortical and subcortical region was reduced by a mean of 45% with MDL 72527 treatment. These results suggest that the polyamine interconversion pathway has an important role in the postischemic increase in putrescine levels and that blocking of this pathway can be neuroprotective against neuronal cell damage after temporary focal cerebral ischemia.

Animals↗
PubMed1999

Traumatic injury to rat brain upregulates neuronal nitric oxide synthase expression and L-[3H]nitroarginine binding.

Overstimulation of N-methyl-D-aspartate (NMDA) receptors is felt to precipitate the neuronal damage following traumatic brain injury (TBI). NMDA receptor-mediated, glutamate-induced excitotoxicity is thought to be mediated via nitric oxide (NO) formed by neuronal nitric oxide synthase (nNOS). The present study examined the mRNA and protein levels of nNOS in the ipsilateral and contralateral cortex of rats as a function of time (5 minutes to 1 week) after controlled cortical impact (CCI) brain injury. Sham-operated rats served as controls. TBI resulted in a significant increase in the levels of nNOS mRNA (1.5- to 2.8-fold, p < .05) between 2 and 4 hours after the injury. There was also a significant increase in the levels of nNOS protein (by 55% to 90%, p < .05) and binding densities of the nNOS-specific ligand L-[3H]nitroarginine (L-[3H]NOARG) (by 35% to 59%, p < .05) between 2 and 12 hours after the injury. Increased nNOS expression and function may contribute to the concomitant excitotoxic neuronal death after TBI.

Animals↗
PubMed1999

Contribution of polyamine oxidase to brain injury after trauma.

OBJECT: The possible role of the polyamine interconversion pathway on edema formation, traumatic injury volume, and tissue polyamine levels after traumatic brain injury (TBI) was studied using an inhibitor of the interconversion pathway enzyme, polyamine oxidase. METHODS: Experimental TBI was induced in Sprague-Dawley rats by using a controlled cortical impact device at a velocity of 3 m/second, resulting in a 2-mm deformation. Immediately after TBI was induced, 100 mg/kg of N1,N4-bis(2,3-butadienyl)-1,4-butanediamine 2HCl (MDL 72527) or saline was injected intraperitoneally. Brain water content and tissue polyamine levels were measured at 24 hours after TBI. Traumatic injury volume was evaluated using 2% cresyl violet solution 7 days after TBI occurred. The MDL 72527 treatment significantly reduced brain edema (80.4+/-0.8% compared with 81.2+/-1.2%, p < 0.05) and injury volume (30.1+/-6.6 mm3 compared with 42.7+/-13.3 mm3, p < 0.05) compared with the saline treatment. The TBI caused a significant increase in tissue putrescine levels at the traumatized site (65.5+/-26.5 nmol/g [corrected] in the cortex and 70.9+/-22.4 nmol/g [corrected] in the hippocampus) compared with the nontraumatized site (7+/-2.4 nmol/g [corrected] in the cortex and 11.4+/-6.4 nmol/g [corrected] in the hippocampus). The increase in putrescine levels in both the traumatized and nontraumatized cortex and hippocampus was reduced by a mean of 60% with MDL 72527 treatment. CONCLUSIONS: These results demonstrate, for the first time, that the polyamine interconversion pathway has an important role in the increase of putrescine levels after TBI and that the polyamine oxidase inhibitors, blockers of the interconversion pathway, can be neuroprotective against edema formation and necrotic cavitation after TBI.

Animals↗
PubMed1998

Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain.

Excess activation of NMDA receptors is felt to participate in secondary neuronal damage after traumatic brain injury (TBI). Increased extracellular glutamate is active in this process and may result from either increased release or decreased reuptake. The two high-affinity sodium-dependent glial transporters [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST)] mediate the bulk of glutamate transport. We studied the protein levels of GLT-1 and GLAST in the brains of rats after controlled cortical impact-induced TBI. With use of subtype-specific antibodies, GLT-1 and GLAST proteins were quantitated by immunoblotting in the ipsilateral and contralateral cortex at 2, 6, 24, 72, and 168 h after the injury. Sham-operated rats served as control. TBI resulted in a significant decrease in GLT-1 (by 20-45%; p < 0.05) and GLAST (by 30-50%; p < 0.05) protein levels between 6 and 72 h after the injury. D-[3H]Aspartate binding also decreased significantly (by 30-50%; p < 0.05) between 6 and 72 h after the injury. Decreased glial glutamate transporter function may contribute to the increased extracellular glutamate that may mediate the excitotoxic neuronal damage after TBI. This is a first report showing altered levels of glutamate transporter proteins after TBI.

ATP-Binding Cassette Transporters↗
PubMed1998

Intraluminal suture occlusion of the middle cerebral artery in Spontaneously Hypertensive rats.

In models of middle cerebral artery occlusion using intraluminal suture, the size and the distribution of ischemic injury vary considerably among laboratories. In transcranial models of cerebral ischemia, a more consistent cerebral ischemic lesion is seen in Spontaneously Hypertensive rats (SHR). In the present study, we performed intraluminal suture occlusion of the MCA in SHR and compared its reproducibility with those in Sprague-Dawley (SD) rats. Male SHR and SD rats were anesthetized with halothane and subjected to 2 h of temporary middle cerebral artery occlusion by an intraluminal suture. Comparisons of regional cerebral blood flow figures taken throughout the experiment and lesion volume figures taken at 24 h after occlusion were made between the two groups. Total lesion volume in the SHR group was 263.6+/-30.5 mm3 (mean +/- SD), significantly larger and less variable than that in the SD group (145.4+/-123.7 mm3, p < 0.02). Throughout the ischemic period there was a tendency for rCBF to be lower in the SHR group than in the SD group. In some animals of both groups, recirculation could not be produced by withdrawal of the suture from the ICA. The mortality rate was 9% in the SD group and 17% in the SHR group. Intraluminal MCA occlusion in SHRs is associated with a more consistent, reliable and reproducible volume of ischemic injury. In the studies of temporary focal cerebral ischemia, this model must be accompanied by the monitoring of regional cerebral blood flow so as to obtain more reliable results.

Age Factors↗
PubMed1997

Characterization of binding sites for the omega3 receptor ligands [3H]PK11195 and [3H]RO5-4864 in human brain.

The kinetics and pharmacology of the isoquinoline and benzodiazepine binding sites of the omega3 or peripheral-type benzodiazepine receptors were studied using the specific ligands [3H] 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin -2-one ([3H]PK11195) and [3H]1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarb oxamide ([3H]RO5-4864), respectively. Binding of both ligands was saturable, reversible, displayed nanomolar affinity, and best fit to a single site model. Occipital cortex and cerebellum displayed highest and lowest densities of binding sites respectively; for both ligands. Bmax values of [3H]PK11195 were several-fold higher than that of [3H]RO5-4864 in all regions studied consistent with their binding to distinct subunits of the human peripheral-type benzodiazepine receptor heteromeric complex. However, the isoquinoline and benzodiazepine ligands were found to be mutually competitive at nanomolar concentrations suggesting allosteric interactions between these two sites. Competition binding experiments showed that the binding of both ligands was displaced by diazepam with Ki values in the nM range, and by clonazepam in the microM range. The novel peripheral-type benzodiazepine receptor ligand 2-(4-fluorophenyl)-N,N-di-n-hexyl-1H-indole-3-acetamide (FGIN1-27) displaced only [3H]PK11195 binding with high potency. Heterogeneity of the two sites is observed, manifested by their differential susceptibility towards detergents and alcohols. Histidine residue modification by diethylpyrocarbonate treatment abolished only [3H]PK11195 binding but had no effect on [3H]RO5-4864 binding. These studies demonstrate that the isoquinoline and benzodiazepine sites on the peripheral-type benzodiazepine receptor in human brain manifest many pharmacological characteristics that are distinct from each other and from rodent brain peripheral-type benzodiazepine receptors.

Allosteric Regulation↗