Biomedical subjects

Jagadeesh S Rao

Publications and source records attributed to Jagadeesh S Rao.

6 recordsLinked to original sources

PubMed2006

RETRACTED: Chronic administration of carbamazepine down-regulates AP-2 DNA-binding activity and AP-2alpha protein expression in rat frontal cortex.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of author Stanley Rapoport, with approval from Biological Psychiatry Editor, John H. Krystal, MD. The National Institutes of Health has found that Dr. Jagadeesh S. Rao engaged in research misconduct by falsifying data in Figures 1, 3, and 5 of the aforementioned manuscript. No other authors were implicated in the data falsification

Animals↗

PubMed2006

Chronic treatment with mood stabilizers increases membrane GRK3 in rat frontal cortex.

BACKGROUND: G-protein receptor kinases (GRKs) are a family of serine/threonine kinases involved in the homologous desensitization of agonist activated G-protein coupled receptors (GPCRs). G-protein coupled receptor supersensitivity, possibly as a result of decreased GRK, has been suggested in affective disorders. METHODS: We used immunobloting to determine if chronic, therapeutically relevant doses of lithium (Li+), carbamazepine (CBZ), and valproate (VPA), would increase GRK2/3 protein levels in rat frontal cortex. RESULTS: Chronic Li+ (24%) and CBZ (44%) significantly increased GRK3 in the membrane but not cytosol fractions. Chronic VPA had no effect on GRK3. G-protein receptor kinase 2 protein levels were unchanged by all treatments. The GRK3 membrane to cytosol ratio was increased significantly in Li+ and CBZ treated rats. CONCLUSIONS: These results show that chronically administered Li+ and CBZ, but not VPA, increase the translocation of GRK3 from cytosol to membrane, possibly correcting supersensitivity of GPCRs in bipolar disorder.

Animals↗

PubMed2005

Down-regulation of brain nuclear factor-kappa B pathway in the cyclooxygenase-2 knockout mouse.

Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. Evidence suggests that neuronal COX-2 gene expression is mainly regulated by the transcription factor nuclear factor kappa-B (NF-kappaB). The present study was undertaken to determine whether there is a shared regulation of NF-kappaB or of nuclear factor of activated T-cells cytoplasmic (NFATc) with COX-2 and whether these transcription factors known to regulate COX-2 expression are altered in brain from COX-2 knockout (COX-2-/-) mice compared to wild type. We found a decrease in NF-kappaB DNA-protein binding activity, which was accompanied by a reduction of the phosphorylation state of both I-kappaBalpha and p65 proteins in the COX-2-/- mice. The mRNA and protein levels of p65 were also reduced in COX-2-/- mice, whereas total cytoplasmic I-kappaB protein level was not significantly changed. Taken together, these changes may be responsible for the observed decrease in NF-kappaB DNA binding activity. NF-kappaB DNA binding activity was selectively affected in the COX-2-/- mice compared to the wild type as there was no significant change in NFATc DNA binding activity. Overall, our data indicate that constitutive brain NF-kappaB activity is decreased in COX-2 deficient mice and suggest a reciprocal coupling between NF-kappaB and COX-2.

Animals↗

PubMed2005

Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat.

RATIONALE: It has been reported that each of three drugs effective in treating bipolar disorder (lithium, carbamazepine, and valproate) decreases the turnover of arachidonic acid (AA, 20:4n-6) in brain phospholipids of the awake rat. It is also known that lithium and carbamazepine do so without decreasing the turnover of docosahexaenoic acid (DHA, 22:6n-3). OBJECTIVE: The aim of this study was to see whether valproate also specifically targets the turnover of AA but not of DHA in brain phospholipids. METHODS: Valproate was administered (200 mg kg(-1), i.p.) to rats for 30 days to produce a therapeutically relevant plasma concentration and then determine its effect compared with that of vehicle on incorporation and turnover rates of DHA in brain phospholipids. In unanesthetized rats that had received valproate or vehicle, [1-14C]DHA was infused intravenously, and arterial blood plasma was sampled until the animal was killed at 5 min; and its brain, after being microwaved, was subjected to chemical and radiotracer analysis. RESULTS: Using equations derived from our fatty acid model, it was found that chronic valproate compared with vehicle did not alter the rate of incorporation or turnover of DHA in brain phospholipids. Valproate-treated animals had higher concentrations of linoleic acid (18:2n-6) in several brain phospholipids, supporting the hypothesis that it alters brain n-6 fatty acid metabolism. CONCLUSIONS: The results, comparable to published findings following chronic administration of lithium and carbamazepine to rats, support the hypothesis that drugs are effective against mania in bipolar disorder act by downregulating incorporation and turnover of AA, but not of DHA, in brain phospholipids.

Acyl Coenzyme A↗

PubMed2005

Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder.

BACKGROUND: The basis for carbamazepine's efficacy in treating bipolar disorder is not agreed on. One hypothesis is that, similar to lithium and valproate (antibipolar drugs), carbamazepine might selectively decrease the kinetics of arachidonic acid (AA) in brain phospholipids. METHODS: To assess whether it targets brain AA kinetics, we administered carbamazepine (25 mg/kg/day, IP) to rats for 30 days and then determined its effect compared with that of vehicle on incorporation and turnover rates of AA and docosahexaenoic acid (DHA) in brain phospholipids. In unanesthetized rats that had received carbamazepine or vehicle, [1-14C]AA or [1-14C]DHA was infused intravenously, and arterial blood plasma was sampled until the animal was killed at 5 min and its brain, after being microwaved, was used for acyl-coenzyme A (acyl-CoA) and phospholipid fatty acid analysis. RESULTS: Chronic carbamazepine, compared with vehicle, decreased the rate of incorporation of AA-CoA (27%-29%) and turnover of AA (25%-27%) but not of DHA-CoA or DHA in brain phospholipids. CONCLUSIONS: The results, which are comparable to published findings after chronic administration of lithium and valproic acid to rats, support the hypothesis that drugs effective against mania in bipolar disorder act by selectively downregulating the incorporation rate of AA-CoA and turnover of AA in brain phospholipids.

Acyl Coenzyme A↗

PubMed2005

Decrease in the AP-2 DNA-binding activity and in the protein expression of AP-2 alpha and AP-2 beta in frontal cortex of rats treated with lithium for 6 weeks.

Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A2 (cPLA2), without affecting secretory sPLA2 or Ca2+-independent iPLA2. We investigated whether transcription factors known to regulate cPLA2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 alpha and AP-2 beta but not of the AP-2 gamma subunits in the frontal cortex. Activating protein 1 (AP-1)-binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC alpha and PKC epsilon, as well as AA-dependent PKC activity. The protein levels of PKC alpha and PKC epsilon were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC alpha and PKC epsilon contributes to lowering the AP-2 activity.

Animals↗