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Biomedical subjects

S K Kulkarni

Publications and source records attributed to S K Kulkarni.

At least 127 records · Page 7Linked to original sources
PubMed1997

Reversal of benzodiazepine inverse agonist FG 7142-induced anxiety syndrome by neurosteroids in mice.

We have previously shown that neurosteroids produce GABA-A receptor mediated antistress, anxiolytic and other behavioral effects in rodents. In the present study, the effects of neuroactive steroids on benzodiazepine receptor inverse agonist FG 7142-induced anxiogenesis were investigated using mirrored chamber and elevated plus-maze paradigms in mice. FG 7142 (5-20 mg/kg) not only produced a dose-dependent reduction in the duration of open arm exploration and the total number of open arm entries, but also increased the latency to enter the mirrored chamber, decreased the number of entries and total time spent in the chamber, indicative of anxiogenic-like effects. Neurosteroids allopregnanolone (0.5 and 1.5 mg/kg) and pregnenolone sulfate (2 mg/kg) significantly reversed the FG 7142 (10 mg/kg)-induced anxiogenic response in both the paradigms, without producing any neurotoxicity. While dehydroepiandrosterone sulfate (1 and 2 mg/kg) failed to influence the anxiogenic effects of FG 7142. The neuroactive steroid progesterone (1-10 mg/kg), and the mitochondrial diazepam binding inhibitor (DBI) receptor agonist 4'-chlordiazepam (0.5 and 1 mg/kg) dose-dependently blocked the FG 7142-induced anxiogenesis in a flumazenil (2 mg/kg)-insensitive manner. The 4'-chlordiazepam-induced reversal response was, however, prevented by pretreatment with PK11195 (2 mg/kg), a selective mitochondrial DBI receptor antagonist. Further, at the anxiolytic doses, these neurosteroids did not produce locomotor inhibition and ataxia. These data suggest that neurosteroids allopregnanolone, pregnenolone sulfate, progesterone and the mitochondrial DBI receptor agonist 4'-chlordiazepam reverses the anxiogenic-like effects of benzodiazepine receptor inverse agonist FG 7142 in the mouse models of anxiety.

Animals↗
PubMed1996

Role of GABA-A and mitochondrial diazepam binding inhibitor receptors in the anti-stress activity of neurosteroids in mice.

Neuroactive steroidal modulation of immobilization-stress and possible involvement of GABA-A and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) has been investigated in mice. Immobilization of mice for 2 h induced intense antinociception, anxiety state, and associated with a fall in adrenal ascorbic acid levels. Pretreatment with high dose of progesterone (10 mg/kg), a precursor of neurosteroids, significantly decreased the stress-induced antinociception, anxiety and fall in adrenal ascorbic acid, while low doses (1 and 5 mg/kg) or hydrocortisone (10 and 100 mg/kg) were ineffective. In contrast, progesterone (1 mg/kg, for 9 days) produced a significant antistress effect, which was blocked by GABA-A antagonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg), but not by flumazenil (2 mg/kg), a specific benzodiazepine (BZD) antagonist. 4'-chlordiazepam (0.1 and 0.25 mg/kg), a specific high affinity MDR agonist, produced significant anti-stress effect in a flumazenil-insensitive manner, but was blocked by pretreatment with PK11195 (1.5 mg/kg), a selective partial agonist of MDR, and with bicuculline (1 mg/kg), a potent GABA-A receptor antagonist. At higher doses, progesterone and 4'-chlordiazepam which are effective in immobilization stress also reduced locomotion. However, lower doses of progesterone (6.5 mg/kg) neither affected locomotion, nor produced any motor toxicity on rota-rod test. At the lower doses, the MDR ligand 4'-chlordiazepam (50 micrograms/kg) decreased locomotor activity, without altering motor toxicity on rota-rod test. Further, the per se effects of these treatments on unstressed mice were not significantly different from those of untreated controls, except for plus-maze test. The antistress profile of progesterone may be attributed to the in vivo production of neurosteroid allopregnanolone, thus resembled that of BZDs. Furthermore, the antistress actions are flumazenil-resistant, reaffirming that there may be an increase in the levels of pregnane neurosteroids in vivo, which may act on a specific allosteric site on GABA-A receptors distinct from BZD site. Because 4'-chlordiazepam binds to MDRs and stimulate mitochondrial neurosteroidogenesis, the anti-stress effects of 4'-chlordiazepam may be imputed to its MDR-induced neurosteroids, which then act on GABA-A receptors. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the antistress actions of neurosteroids and reinforces their ameliorative effect in physiological stress.

Analysis of Variance↗
PubMed1996

Protective effects of GABAergic drugs and other anticonvulsants in lithium-pilocarpine-induced status epilepticus.

Administration of subconvulsive dose of pilocarpine (30 mg/kg s.c.) to rats pretreated with lithium chloride (3 meq/kg i.p.) produced a state of status epilepticus in animals. The animals showed characteristic symptoms of generalized convulsions, wet dog shakes (WDS), forelimb clonus and falling back. The symptoms of status epilepticus (SE) developed within 26.8 +/- 3.6 min after administering pilocarpine and these symptoms continued uninterrupted. The phenomenon was totally reproducible, with a consistent latency of onset of seizures and a high mortality rate. The symptoms were blocked by atropine, scopolamine and the GABAergic agents GABA, sodium valproate, (+)-baclofen and clonazepam when given prior to pilocarpine, but not when administered 30 min after pilocarpine administration.

Animals↗
PubMed1996

Gastric antiulcer activity of UL-409 in rats.

Effect of UL-409, a multiconstituent herbal preparation was evaluated on different models of gastric ulcers in rats. In doses 25, 50 and 100 mg/kg. p.o. it significantly reduced the gastric secretory volume and ulcer index in pylorus ligated rats, and showed significant mucoprotective effect at 100 mg/kg dose on both acute and chronic treatment. UL-409(50 and 100 mg/kg doses) prevented immobilization induced gastric ulceration and showed significant mucosal protection. In forced swimming induced ulcers, UL-4093(50 and 100 mg/kg) completely abolished the ulcerogenesis and strengthened the mucosal barrier. It also protected the indomethacin-induced gastric ulcers and significantly increased the mucosal content. Cimetidine (10 mg/kg) and diazepam (20 mg/kg) were used for comparison. The results indicate that UL-409 has anti-ulcerogenic effects due to its mucoprotective effect. The preparation can be used alone or in combination with other ulcer healing agents.

Animals↗
PubMed1996

Influence of antidepressant drugs on learning and memory paradigms in mice.

Effect of antidepressant drugs (amitriptyline, imipramine and fluoxetine) on cognitive functions, impaired by the muscarinic antagonist scopolamine were investigated in mice. The changes in learning and memory tasks were studied using transfer latency on elevated plus maze and employing number of descents in passive avoidance paradigms. Amitriptyline and imipramine showed significant memory impairment. They also potentiated scopolamine-induced memory deficit in a significant way. Amitriptyline and imipramine impair cognitive function possibly due to their anticholinergic properties. Fluoxetine, a newer antidepressant, however showed no effect on learning and memory. It significantly reversed the scopolamine-induced memory impairment in both the tests. Fluoxetine with no anticholinergic property may prove to be a better drug in endogenous depression in elderly patients.

Aged↗
PubMed1996

Prevention of morphine discontinuation phenomenon in mice by ondansetron, a selective 5-HT3 antagonist.

The effects of ondansetron, a highly potent and selective 5-HT3 receptor antagonist, in the prevention of tolerance to and dependence on morphine were studied in mice using a 9-day schedule. Chronic administration of morphine (10 mg/kg i.p. twice daily for 9 days) produced tolerance to the analgesic effects and animals showed withdrawal jumps on day 10 when challenged with naloxone (2 mg/kg). Chronic treatment with ondansetron (0.01 and 0.1 mg/kg) followed by saline on days 1-9 failed to produce any significant change in tail-flick latency in the saline-pretreated group. Repeated administration of ondansetron (0.01 and 0.1 mg/kg) for 9 days, however, attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). The higher dose of ondansetron (0.1 mg/kg) also suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal on day 10 of testing.

Analgesics, Opioid↗
PubMed1995

Role of D1/D2 dopamine and N-methyl-D-aspartate (NMDA) receptors in morphine tolerance and dependence in mice.

Chronic treatment with the dopamine (DA) agonist B-HT 920 (0.25-1 mg/kg) or bromocriptine (1 mg/kg) followed by morphine (10 mg/kg) on days 1-9 prevented the development of tolerance to the antinociceptive effect of morphine as measured by the tail-flick test in mice, but failed to suppress the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Repeated administration of SKF 38393 (5 mg/kg) followed by morphine for 9 days significantly reduced naloxone-precipitated jumps on day 10 but failed to produce any significant change in tail-flick latency from the saline-pretreated group of mice on days 9 and 10 of testing. Repeated administration of B-HT 920 or bromocriptine enhanced the ability of MK-801 to attenuate the development of morphine tolerance and dependence while SKF 38393 failed to do so. The above data suggest a preferential role of D2 DA receptors in morphine tolerance and D1 receptors in the development of morphine dependence. D2 DA receptor stimulation may also play an important role in enhancing the effectiveness of MK-801 in the treatment of opiate tolerance and dependence.

Animals↗
PubMed1995

Pentylenetetrazol-induced kindling in animals: protective effect of BR-16A.

Repeated administration of pentylenetetrazol (PTZ, 30 mg/kg, thrice a week) to mice for 9 weeks and subsequent challenge of the animals with the same dose of PTZ on the last chronic dose produced chemical kindling. The mice showed myoclonic jerks, clonus, Straub's tail, falling back response and full blown convulsions. The anticonvulsant profile of chronic administration of BR-16A (100 and 500 mg/kg) was studied in this model of epilepsy. BR-16A offered protection against PTZ-induced chemical kindling. The per cent animals showing myoclonic jerks and clonus was reduced to 40 and 34 with 100 mg/kg and 54 and 27 with 500 mg/kg of BR-16A, respectively. The protective effect was compared with diazepam (1 mg/kg, ip). The results demonstrated GABAA receptor mediated PTZ-induced kindling and protective effect of BR-16A therein.

Animals↗
PubMed1995

Amniotic fluid index in the management of the postdates pregnancy.

This is a prospective evaluation of the relationship between the amniotic fluid index (AFI) and perinatal outcome in 55 postdates pregnancies. The gravid abdomen was divided into four quadrants, using real-time ultrasound with a 3.5 mHz transducer, the largest pocket of amniotic fluid in each quadrant was measured and their sum totalled to arrive at the amniotic fluid index. AFI in this study ranged from 2.8 cm to 22.6 cm. The mean for 41 weeks was 13.52 +/- 4.6 cm and for 42 weeks, 9.93 +/- 4.37 cm. Oligohydramnios was noted in four patients, AFI less than 5.3 cm. Two of these cases developed intrapartum foetal distress and had Caesarean Section. All four babies were admitted with meconium aspiration and one died from this complication.

Amniotic Fluid↗
PubMed1995

Lithium-pilocarpine neurotoxicity: a potential model of status epilepticus.

Convulsive status epilepticus (SE) is clinically defined as prolonged electrical and clinical seizure activity in which the patient does not regain consciousness to a normal alert state between repeated tonic-clonic attacks. The disorder is a neurological emergency associated with a mortality rate of 10-12% and an even greater morbidity. Seizures represent one of the most severe in vivo stimulatory stresses that the brain is exposed to and generalized status epilepticus represents a very severe form of seizures. The International Classification of Seizures has defined this condition as "a condition characterized by an epileptic seizure that is so frequent or so prolonged as to create a fixed and lasting condition". During SE, high-amplitude, high-frequency electrical activity lasting at least 5 min is seen in the EEG. Continuous seizure activity in itself will result in progressive brain injury. The longer the condition of SE, the more difficult it is to control and the more likely it is to result in permanent neuronal damage. Therefore, SE is an emergency situation requiring prompt medical attention if severe permanent brain damage or death is to be prevented. SE often occurs in individuals with a history of seizures, in whom there are neural substrates already predisposed towards supporting seizure activity.

Animals↗
PubMed1994

Reversal of diazepam withdrawal induced hyperactivity in mice by BR 16-A (Mentat), a herbal preparation.

Abrupt cessation of chronic treatment of diazepam (20 mg/kg/day for 21 days) produced withdrawal reactions. BR 16-A, a multicomponent herbal preparation shown to reverse the withdrawal reactions to opiates was studied against diazepam induced withdrawal reactions in mice. Acute dose of diazepam (20 mg/kg) produced a decrease in the ambulatory and total activity. However, chronic administration for 21 days produced tolerance and no significant change in the ambulatory and total activity. On abrupt termination of diazepam treatment after 21 days, the animals showed anxiety and excitement as there was an increase in ambulatory and total activity. The withdrawal excitement was highest at 72 hr of the last dose of diazepam. Concomittant administration of BR 16-A (100 and 500 mg/kg) reversed the acute effect of diazepam in a dose dependent manner. Similarly, chronic administration of BR 16-A (100 and 500 mg/kg/day for 21 days) with diazepam (20 mg/kg/day for 21 days) also reversed the withdrawal induced hyperambulation and total activity. Chronic administration of BR 16-A per se had no significant effect on the ambulatory and total activity, however, in acute doses, BR 16-A (100 and 500 mg/kg) produced a dose dependent increase in the ambulatory and total activity. BR 16-A with its CNS profile of activity could be a useful preparation in the management of substances of abuse.

Animals↗
PubMed1994

Dopamine receptor mediated antidepressant action of B-HT 920 in mice.

Possible involvement of dopaminergic (DAergic) system in forced swimming-induced immobility (despair behaviour) was investigated in mice. B-HT 920 (0.05 and 0.1 mg/kg), a post-synaptic DAergic agonist, produced a dose dependent reduction in immobility period, which was sensitive to blockade by haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). This effect was also blocked by alpha 2 antagonist yohimbine (5 mg/kg). SKF 38393 (5 mg/kg), a D1-DA agonist potentiated the action of B-HT 920. Reserpinization (2 mg/kg, 24 hr prior) produced despair immobility in mice. When a low dose of B-HT 920 (0.05 mg/kg) was given to reserpinized animals, the duration of immobility period was further increased. But on the other hand, a higher dose (0.1 mg/kg) of it reduced reserpine-induced immobility. Desipramine (5 and 10 mg/kg), elicited a dose dependent reduction in the immobility period, which was sensitive to blockade by sulpiride (100 mg/kg). Desipramine (10 mg/kg) showed a diphasic response in combination with B-HT 920, i.e., a potentiation of the response due to a low dose of B-HT 920 (0.05 mg/kg) and an antagonism of the response due to a higher dose of B-HT 920 (0.1 mg/kg), respectively. SKF 38393 (5 mg/kg), potentiated the action of desipramine (5 mg/kg). SKF 38393 (5 mg/kg) further potentiated the action of desipramine (5 mg/kg) and B-HT 920 (0.05 mg/kg). These observations suggests that B-HT 920 reduces behavioural immobility by DAergic mechanism and desipramine also modulates D2-DA receptors in its anti-depressant action.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

On the characterization of dopamine-induced contractile response of rat anococcygeus muscle preparation.

Presence of specific dopamine (DA) receptors and their characterization was attempted in rat anococcygeus muscle preparation. Dopamine (10(-6) M) and B-HT 920 (10(-6) M) produced concentration dependent contractions of the rat anococcygeus muscle preparation. The response of DA was shifted towards right in presence of haloperidol (10(-6) M; pA2 = 6.8) and sulpiride (10(-4) M) in a competitive manner. Alpha 2 antagonists yohimbine (10(-5) M) and idazoxan (10(-5) M) blocked the response to DA in a competitive manner, while alpha 1 antagonist prazosin (10(-5) M) completely blocked the response to DA. SCH 23390 (10(-5) M), a D1 DA antagonist potentiated the response to DA. Reserpinization (5 mg/kg, 24 hr prior) brought about a shift towards the right, and this response was similarly blocked by haloperidol, sulpiride and yohimbine without affecting the maximum response. Desipramine (10(-5) M) blocked the response of DA in a non-competitive manner. Pretreatment of animals with desipramine (10 mg/kg) followed by reserpine, brought about a reversal of action of reserpine. The response to B-HT 920 (10(-6) M), was blocked similarly by haloperidol and yohimbine. However, the effect of desipramine was more pronounced when compared to DA per se. SKF 38393, a D1 DA agonist, potentiated the response to B-HT 920. The findings suggest the presence of both D1 and D2 DA receptors in rat anococcygeus muscle and that DA also acts on adrenergic receptors to produce a contractile response of this muscle preparation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Autonomously replicating single-copy episomes in Trypanosoma brucei show unusual stability.

We have obtained several autonomously replicating plasmids in procyclic Trypanosoma brucei. Two of these have been analyzed in detail. Both exist as monomeric single-copy episomes, which nevertheless demonstrate significant stability. These episomes transform procyclics at frequencies that are at least 60-fold higher than those achieved earlier with non-replicating molecules. A modified version of one of these episomes is able to replicate autonomously in bloodstream form T. brucei but it is unstable in this developmental stage of the organism. These episomes will prove useful as shuttle vectors, in functional complementation studies, in the construction of promoter-traps for the isolation of transcriptional promoters in T. brucei, and importantly, as models for the analysis of DNA replication in this ancient eukaryotic lineage.

Animals↗