Pharmacological Preconditioning by Milrinone: Memory Preserving and Neuroprotective Effect in Ischemia-Reperfusion Injury in Mice

Reetu Saklani,Amteshwar Jaggi,Nirmal Singh 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.7

We tested the neuroprotective effect of milrinone, a phosphodiesterase III inhibitor, in pharmacological preconditioning. Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h produced ischemia-reperfusion (I/R) cerebral injury in male Swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using the Morris water maze test, and motor coordination was evaluated using the inclined beam walking test, rota-rod test, and lateral push test. Milrinone (50 μg/kg & 100 μg/kg i.v.) was administered 24 h before surgery in a separate group of animals to induce pharmacological preconditioning. I/R increased cerebral infarct size and impaired memory and motor coordination. Milrinone treatment significantly decreased cerebral infarct size and reversed I/R-induced impairments in memory and motor coordination. This neuroprotective effect was blocked by ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker. These findings indicate that milrinone preconditioning exerts a marked neuroprotective effect on the ischemic brain, putatively due to increased intracellular calcium levels activating calcium-sensitive signal transduction cascades.

Effect of Neurosteroid Modulation on Global Ischaemia-Reperfusion-Induced Cerebral Injury in Mice

Amarjot Kaur Grewal,Amteshwar Singh Jaggi,Avtar Ch,Rana,Nirmal Singh 대한생리학회-대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.6

The present study was designed to investigate the putative effect of neurosteroid modulation on global ischaemia-reperfusion-induced cerebral injury in mice. Bilateral carotid artery occlusion followed by reperfusion, produced a significant rise in cerebral infarct size along with impairment of grip strength and motor coordination in Swiss albino mice. Administration of carbamazepine (16 mg/kg, i.p.) before global cerebral ischaemia significantly attenuated cerebral infarct size and improved the motor performance. However, administration of indomethacin (100 mg/kg, i.p.) attenuated the neuroprotective effect of carbamazepine. Mexiletine (50 mg/kg, i.p.) did not produce significant neuro-protective effect. It may be concluded that the neuroprotective effect of carbamazepine may be due to increase in synthesis of neurosteroids perhaps by activating enzyme (3α HSD) as indomethacin attenuated the neuroprotective effect of carbamazepine. The sodium channel blocking effect of car-bamazepine may not be involved in neuroprotection as mexiletine, a sodium channel blocker, did not produce significant neuroprotective effect.

Ameliorative Effect of a Selective Endothelin ETA Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Gautamjeet S Mangat,Amteshwar S. Jaggi,Nirmal Singh 대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.3

The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentanon hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administeredfor 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5th to8th week of L-methionine treatment). On 52nd day onward, the animals were exposed to the Morriswater maze (MWM) for testing their learning and memory abilities. Vascular endothelial function,serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione(GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction,decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levelsand AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment oflearning, memory, endothelial dysfunction, and changes in various biochemical parameters. Theseeffects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan,a selective ETA receptor antagonist may be considered as a potential pharmacological agentfor the management of hyperhomocysteinemia-induced vascular dementia.

Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

Kumar, Rohit,Jaggi, Amteshwar Singh,Singh, Nirmal The Korean Society of Pharmacology 2010 The Korean Journal of Physiology & Pharmacology Vol.14 No.5

The present study was undertaken to explore the potential of erythropoietin in memory deficits of mice. Memory impairment was produced by scopolamine (0.5 mg/kg, $i.p.$) and intracerebroventricular streptozotocin (i.c.v STZ, 3 mg/kg, $10{\mu}l$, $1^{st}$ and $3^{rd}$ day) in separate groups of animals. Morris water-maze test was employed to assess learning and memory. The levels of brain thio-barbituric acid reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess degree of oxidative stress. Brain acetylcholinesterase enzyme (AChE) activity was also measured. Scopolamine/streptozotocin administration induced significant impairment of learning and memory in mice as indicated by marked decrease in Morris water-maze performance. Scopolamine/streptozotocin administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (an increase in TBARS and a decrease in GSH) levels. Treatment of erythropoietin (500 and 1,000 IU/Kg i.p.) significantly reversed scopolamine- as well as streptozotocin-induced learning and memory deficits along with attenuation of those-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that erythropoietin exerts a beneficial effect in memory deficits of mice possibly through its multiple actions including potential anti-oxidative effect.

Effect of Neurosteroid Modulation on Global Ischaemia-Reperfusion-Induced Cerebral Injury in Mice

Grewal, Amarjot Kaur,Jaggi, Amteshwar Singh,Rana, Avtar Chand,Singh, Nirmal The Korean Society of Pharmacology 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.6

The present study was designed to investigate the putative effect of neurosteroid modulation on global ischaemia-reperfusion-induced cerebral injury in mice. Bilateral carotid artery occlusion followed by reperfusion, produced a significant rise in cerebral infarct size along with impairment of grip strength and motor coordination in Swiss albino mice. Administration of carbamazepine (16 mg/kg, i.p.) before global cerebral ischaemia significantly attenuated cerebral infarct size and improved the motor performance. However, administration of indomethacin (100 mg/kg, i.p.) attenuated the neuroprotective effect of carbamazepine. Mexiletine (50 mg/kg, i.p.) did not produce significant neuroprotective effect. It may be concluded that the neuroprotective effect of carbamazepine may be due to increase in synthesis of neurosteroids perhaps by activating enzyme ($3{\alpha}$ HSD) as indomethacin attenuated the neuroprotective effect of carbamazepine. The sodium channel blocking effect of carbamazepine may not be involved in neuroprotection as mexiletine, a sodium channel blocker, did not produce significant neuroprotective effect.

Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

Rohit Kumar,Nirmal Singh,Amteshwar Singh Jaggi 대한약리학회 2010 The Korean Journal of Physiology & Pharmacology Vol.14 No.5

The present study was undertaken to explore the potential of erythropoietin in memory deficits of mice. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) and intracerebroventricular streptozotocin (i.c.v STZ, 3 mg/kg, 10 μl, 1st and 3rd day) in separate groups of animals. Morris watermaze test was employed to assess learning and memory. The levels of brain thio-barbituric acid reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess degree of oxidative stress. Brain acetylcholinesterase enzyme (AChE) activity was also measured. Scopolamine/streptozotocin administration induced significant impairment of learning and memory in mice as indicated by marked decrease in Morris water-maze performance. Scopolamine/streptozotocin administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (an increase in TBARS and a decrease in GSH) levels. Treatment of erythropoietin (500 and 1,000 IU/Kg i.p.) significantly reversed scopolamine- as well as streptozotocin-induced learning and memory deficits along with attenuation of those-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that erythropoietin exerts a beneficial effect in memory deficits of mice possibly through its multiple actions including potential anti-oxidative effect.

Ameliorative Effect of a Selective Endothelin $ET_A$ Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Mangat, Gautamjeet S.,Jaggi, Amteshwar S.,Singh, Nirmal The Korean Society of Pharmacology 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.3

The present study was designed to investigate the efficacy of selective $ET_A$ receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from $5^{th}$ to $8^{th}$ week of L-methionine treatment). On $52^{nd}$ day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective $ET_A$ receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

Ameliorative Effect of a Selective Endothelin ET_A Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

Gautamjeet S Mangat,Amteshwar S Jaggi,Nirmal Singh 대한생리학회-대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.3

The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5^th to 8^th week of L-methionine treatment). On 52^nd day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced gluta-thione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ET_A receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.

A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents

Puneet Kaur Randhawa,Kavinder Singh,Amteshwar Singh Jaggi 대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.4

Ulcerative colitis and Crohn’s disease are a set of chronic, idiopathic, immunological and relapsinginflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, developmentof various animal models provides new insights to unveil the onset and the progression of IBD. Variouschemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closelymimic morphological, histopathological and symptomatical features of human IBD. Among thechemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazoloneinduced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBSelicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response ofTh-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. Thepresent review discusses the methodology and rationale of using various chemical-induced colitismodels for evaluating the pathogenesis of IBD.

A Review on Renal Toxicity Profile of Common Abusive Drugs

Varun Parkash Singh,Nirmal Singh,Amteshwar Singh Jaggi 대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.4

Drug abuse has become a major social problem of the modern world and majority of these abusive drugs or their metabolites are excreted through the kidneys and, thus, the renal complications of these drugs are very common. Morphine, heroin, cocaine, nicotine and alcohol are the most commonly abused drugs, and their use is associated with various types of renal toxicity. The renal complications include a wide range of glomerular, interstitial and vascular diseases leading to acute or chronic renal failure. The present review discusses the renal toxicity profile and possible mechanisms of commonly abused drugs including morphine, heroin, cocaine, nicotine, caffeine and alcohol.