Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic r... more Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC (μM) values with that of the standard drug sodium cromoglycate (IC = 0.489 ± 0.003 μM), compounds with bulky groups like heptyl (compound 9; IC = 0.389 ± 0.015 μM) and octyl (compound 10; IC = 0.354 ± 0.023 μM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (...
The present study was designed to investigate the outcome of combination of Calcineurin (CaN) inh... more The present study was designed to investigate the outcome of combination of Calcineurin (CaN) inhibitor (Tacrolimus) and Protein Kinase A (PKA) activator (Forskolin), in mouse models of experimental dementia. Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] was used to induce memory deficits in NIH mice, while aged mice separately taken served as a natural model of dementia. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. A battery of biochemical and histopathological studies was also performed. Brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS); myeloperoxidase (MPO) levels; acetylcholinestrase (AChE) activity was measured to assess extent of oxidative stress, inflammation and cholinergic activity respectively. Donepezil served as a positive control in this study. STZ (i.c.v.) and aging results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ ...
A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated... more A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated for Acetylcholinesterase (AChE) inhibitory activity integrated with advanced glycation end products (AGEs) inhibitory and antioxidant potential. Most of the derivatives inhibited AChE in nanomolar IC50 range along with good AGEs inhibitory and radical scavenging activity. Among them, 7m, strongly inhibited AChE (IC50 = 5.87 nM) and found to be potent as compared to the reference drug donepezil (IC50 = 12.7 nM). Its potent inhibitory activity has been justified by docking analysis that revealed its dual binding characteristic with both CAS (catalytic active site) and PAS (peripheral anionic site) of AChE, simultaneously. Additionally, this compound also displayed ability to prevent advanced glycation end products formation (IC50 = 23.0 µM) with additional radical scavenging property (IC50 = 37.12 nM). It (7m) also ameliorated scopolamine induced memory deficit in mice employing Morris water maze test. Thus, flavonoids might be the promising lead compounds as potential polyfunctional anti-Alzheimer's agents.
The present study was designed to investigate the role of mast cells and mast cell-derived histam... more The present study was designed to investigate the role of mast cells and mast cell-derived histamine in vincristine-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (100 μg/kg, i.p.) over a period of 10 days, with a break of 2 days, and pain behavioural estimations including pin prick, hot plate and acetone spray tests were performed to assess mechanical and heat hyperalgesia and cold allodynia, respectively, on days 0, 14 and 28. Mast cell stabilizer, sodium cromoglycate, H1 receptor antagonist promethazine and H2 receptor antagonist ranitidine were administered over a period of 12 days. Administration of vincristine resulted in significant development of heat and mechanical hyperalgesia as well as cold allodynia. Furthermore, the pain observed was markedly elevated on the 28th day in comparison to the 14th day. Administration of sodium cromoglycate, promethazine and ranitidine significantly reduced mechanical and heat hyperalgesia and cold allodynia. However, the pain-attenuating effects of ranitidine were significantly less as compared to sodium cromoglycate and promethazine, which suggests that H1 receptors play a more important role than H2 receptors in vincristine-induced neuropathic pain. It may be concluded that vincristine may degranulate mast cells to release inflammatory mediators, particularly histamine which may act through H1 (primarily H1) and H2 receptors to induce neuropathic pain.
Reactive oxygen species are the reactive molecules that are derived from molecular oxygen and pla... more Reactive oxygen species are the reactive molecules that are derived from molecular oxygen and play an important role as redox signaling molecules to confer cardioprotection. Various scientists have demonstrated the key role of redox signaling in cardioprotection by showing a transient increase in their levels during remote ischemic preconditioning (RIPC) phase. The transient increase in reactive oxygen species levels during remote preconditioning phase may take place either through activation of KATP channels or through increased nitric oxide (NO) production. A transient increase in reactive oxygen species during preconditioning may also increase the expression of heat shock proteins (HSP), the level of antioxidant enzymes and decrease the expression of inflammatory genes (Egr-1) during ischemia-reperfusion phase to confer cardioprotection. The present review describes the role of redox signaling in RIPC-induced cardioprotective effect with possible mechanisms.
Mast cells are immunological cells that are diversely distributed in different parts of the body.... more Mast cells are immunological cells that are diversely distributed in different parts of the body. Their role in various pathological conditions such as hypersensitivity, atherosclerosis, pulmonary hypertension, and male infertility has been reported by different scientists. Apart from these, a number of studies have shown their important role in pathogenesis of neuropathic pain of diverse aetiology. They have been found to release active mediators, primarily histamine and serotonin on degranulation in response to different stimuli including chemical, nerve damage, toxin or disease-related conditions. The mast cells stabilizer has shown pain attenuating effects by preventing degranulation of mast cells. Similarly, compound 48/80 (first dose 200 μg/100 g and after 6-h interval, second dose of 500 μg/100 g) caused the degranulation of the accumulated endoneurial histamine and 5-HT antagonists have shown pain relieving effects by attenuating the effects of histamine and serotonin, respe...
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, Jan 3, 2017
The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, i... more The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, in chronic constriction injury-induced neuropathic pain. Chronic Constriction Injury was performed by putting four loose ligatures around the sciatic nerve. Pain was assessed by determining mechanical hyperalgesia, cold allodynia and heat hyperalgesia on 7th and 14th day post surgery. Perampanel (3mg and 6mg/kg, p.o.) was administered 30min before pain assessment test on 14th day post-surgery. CCI led to significant development of pain and peak symptoms were observed on 14th day. Perampanel significantly attenuated CCI-induced mechanical hyperalgesia, cold allodynia and heat hyperalgesia, at different time intervals 30, 60, 90, 120min, with more substantial effect observed at dose of 6mg/kgNaloxone was administered in CCI subjected rats before perampanel treatment to explore the potential role of opioids in anti-nociceptive effects of perampanel. Naloxone decreased the pain attenuating ef...
Journal of cardiovascular pharmacology and therapeutics, 2017
Remote ischemic preconditioning (RIPC) is an innovative treatment strategy that alleviates ischem... more Remote ischemic preconditioning (RIPC) is an innovative treatment strategy that alleviates ischemia-reperfusion injury, whereby short episodes of regional ischemia and reperfusion delivered to remote organs including hind limb, kidney and intestine, and so on provide protection to the heart. The RIPC is known to reduce infarct size, serum levels of cardiac enzymes, and myocardial dysfunction in various animal species as well as in patients. There have been a large number of studies suggesting that the ATP-sensitive potassium channels (KATP channel) play a significant role as a mediator or end effector in RIPC. The present review discusses the role of KATP channels and possible mechanisms in RIPC-induced cardioprotection.
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mecha... more The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.
The present study has been designed to investigate the possible role of histaminergic pathway in ... more The present study has been designed to investigate the possible role of histaminergic pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo). Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 hr was employed to produce I/R induced cerebral injury in NIH mice. iPoCo involving three episodes of carotid artery occlusion and reperfusion of 10 sec each, was instituted immediately after BCAO just before prolonged reperfusion. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water maze (MWM) test. Rota rod test, inclined beam walking test and neurological severity score (NSS) were performed to assess motor in-coordination and sensorimotor abilities. Brain acetylcholine esterase (AChE) activity, brain myeloperoxidase (MPO) activity, brain thiobarbituric acid reactive species (TBARS) and glutathione level (GSH) were also estimated. BCAO produced a significant rise in cerebra...
The genus Ocimum (family Lamiaceae) has been revered for its diverse biological activities. Vario... more The genus Ocimum (family Lamiaceae) has been revered for its diverse biological activities. Various species have been used traditionally to treat CNS disorders and are proven to have neuroprotective effect that is often attributed to their significant antioxidant activity. Ocimum kilimandscharicum (Karpoora Thulasi), a prominent member of this genus is reported to have marked antioxidant activity but its neuroprotective potential has not been explored. Thus, present study was designed to evaluate the cerebroprotective effect of O. kilimandscharicum leaf extract (OKLE) in mice against ischemia reperfusion (I-R) induced brain injury. Bilateral common carotid artery occlusion (BCCAO) for 15min followed by 24h reperfusion was used to induce brain damage in Swiss Albino mice. Animals were treated with OKLE (200 and 400mg/kg, po) once daily for 7days after I-R. Morris water maze and elevated plus maze tests were used to assess long and short term memory while neurological severity score was used to determine motor coordination. Histopathological evaluation (TTC staining) along with brain biochemical parameters (TBARS, reduced GSH and SOD activity) were determined to outline neuroprotective mechanism of OKLE. I-R resulted in marked cognitive impairments, motor incoordination in mice, significant brain damage and increased oxidative stress. Treatment with OKLE produced functional recovery in mice which is manifested by improved memory and motor coordination; reduced cerebral infarct size and brain oxidative stress (TBARS levels) and elevated endogenous antioxidants (reduced GSH and SOD activity). In addition, OKLE showed DPPH radical scavenging and reducing power in-vitro. These results show that O. kilimandscharicum mitigated the neurodegenerative changed induced by I-R in mice probably due to its antioxidant activity.
Chronic pain is broadly classified into somatic, visceral or neuropathic pain depending upon the ... more Chronic pain is broadly classified into somatic, visceral or neuropathic pain depending upon the location and extent of pain perception. Evidences from different animal studies suggest that inflammatory or neuropathic pain is associated with altered acetylation and deacetylation of histone proteins, which result in abnormal transcription of nociceptive processing genes. There have been a number of studies indicating that nerve injury up-regulates histone deacetylase enzymes, which leads to increased histone deacetylation and induce chronic pain. Treatment with histone deacetylase inhibitors relieves pain by normalizing nerve injury-induced down regulation of metabotropic glutamate receptors, glutamate transporters, glutamic acid decarboxylase 65, Neuron restrictive silencer factor and Serum and glucocorticoid inducible kinase 1. On the other hand, a few studies refer to increased expression of histone acetylase enzymes in response to nerve injury that promotes histone acetylation leading to pain induction. Treatment with histone acetyl transferase inhibitors have been reported to relieve chronic pain by blocking the up-regulation of chemokines and cyclooxygenase-2, the critical factors associated with histone acetylation-induced pain. The present review describes the dual role of histone acetylation/deacetylation in development or attenuation of neuropathic pain along with the underlying mechanisms.
There is growing preclinical as well as clinical evidence supporting remote ischemic precondition... more There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoi...
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but... more The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but its mechanisms still remain to be explored. Therefore, the present study was aimed to explore the possible involvement of 5-lipoxygenase-derived leukotrienes in RIPC. The hind limb was tied by a pressure cuff and was subjected to four episodes of inflation and deflation (5min each) to induce remote hind-limb preconditioning. Thereafter, the hearts were isolated and were subjected to global ischemia (30min) followed by reperfusion (120min) on the Langendorff apparatus. The extent of myocardial injury was assessed by measuring lactate dehydrogenase (LDH) and creatine kinase (CK) levels in the coronary effluent; the infarct size using TTC staining, and the hemodynamic parameters including LVDP, dp/dtmax and dp/dtmin. RIPC significantly decreased ischemia and reperfusion-induced increase in LDH, CK release, infarct size and improved LVDP, dp/dtmax and dp/dtmin. Administration of montelukast...
Memory, one of the most complex functions of the brain comprises of multiple components such as p... more Memory, one of the most complex functions of the brain comprises of multiple components such as perception, registration, consolidation, storage, retrieval and decay. The present study was undertaken to evaluate the impact of different training sessions on the retention capacity of rats. The capacity of retention of learnt task was measured using exteroceptive behavioral models such as Hexagonal swimming pool apparatus, Hebb-Williams maze and Elevated plus-maze. A total of 150 rats divided into fifteen groups were employed in the present study. The animals were subjected to different training sessions during first three days. The ability to retain the learned task was tested after single, sub-acute, acute, sub-chronic and chronic exposure to above exteroceptive memory models in separate groups of animals. The memory score of all animals was recorded after 72 h, 192 h and 432 h of their last training trial. Rats of single exposure group did not show any effect on memory. Sub-acute training group animals showed improved memory up to 72 h only, where as in acute and sub-chronic training groups this memory improvement was extended up to 192 h. The rats, which were subjected to chronic exposures showed a significant improvement in retention capacity that lasted up to a period of eighteen days. These observations suggest that repeated rehearsals at regular intervals are probably necessary for consolidation of long-term memory. It was observed that sub-acute, acute and sub-chronic exposures, improved the retrieval ability of rats but this memory improving effect was short lived. Thus, rehearsal or training plays a crucial role in enhancing one's capacity of retaining the learnt information.
The present study investigated the role of N-methyl-D-aspartate (NMDA) receptors in pioglitazone-... more The present study investigated the role of N-methyl-D-aspartate (NMDA) receptors in pioglitazone-mediated protection against renal ischemia reperfusion injury (IRI) in rats. Male wistar rats were subjected to 40 min of bilateral renal ischemia followed by reperfusion for 24 h to induce kidney injury. The renal damage was evaluated by measuring serum creatinine, creatinine clearance, blood urea nitrogen, uric acid, electrolytes, and microproteinuria in rats. Oxidative stress in renal tissues was quantified in terms of myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione level. Hematoxylin-eosin and periodic acid Schiff staining of renal tissues were performed to observe histological changes. Pioglitazone (20 and 40 mg/kg) was administered 1 h prior to ischemia in rats. In separate groups, NMDA agonists, glutamic acid (200 mg/kg), and spermidine (20 mg/kg) were administered 1 h prior to pioglitazone treatment, followed by renal IRI in rats. Ischemia reperfusion resulted in marked renal damage with significant changes in serum and urine parameters along with marked oxidative stress and histological changes in kidneys. Pioglitazone treatment afforded anti-oxidant effect and renoprotection in a dose-dependent manner in rats. Pioglitazone-mediated renoprotection was attenuated by glutamic acid and spermidine pretreatment in rats, which indicated the role of NMDA receptors in pioglitazone-mediated protection. It is concluded that NMDA antagonism serves as one of the mechanisms in pioglitazone-mediated protection against renal IRI in rats.
Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic r... more Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC (μM) values with that of the standard drug sodium cromoglycate (IC = 0.489 ± 0.003 μM), compounds with bulky groups like heptyl (compound 9; IC = 0.389 ± 0.015 μM) and octyl (compound 10; IC = 0.354 ± 0.023 μM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (...
The present study was designed to investigate the outcome of combination of Calcineurin (CaN) inh... more The present study was designed to investigate the outcome of combination of Calcineurin (CaN) inhibitor (Tacrolimus) and Protein Kinase A (PKA) activator (Forskolin), in mouse models of experimental dementia. Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] was used to induce memory deficits in NIH mice, while aged mice separately taken served as a natural model of dementia. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. A battery of biochemical and histopathological studies was also performed. Brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS); myeloperoxidase (MPO) levels; acetylcholinestrase (AChE) activity was measured to assess extent of oxidative stress, inflammation and cholinergic activity respectively. Donepezil served as a positive control in this study. STZ (i.c.v.) and aging results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ ...
A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated... more A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated for Acetylcholinesterase (AChE) inhibitory activity integrated with advanced glycation end products (AGEs) inhibitory and antioxidant potential. Most of the derivatives inhibited AChE in nanomolar IC50 range along with good AGEs inhibitory and radical scavenging activity. Among them, 7m, strongly inhibited AChE (IC50 = 5.87 nM) and found to be potent as compared to the reference drug donepezil (IC50 = 12.7 nM). Its potent inhibitory activity has been justified by docking analysis that revealed its dual binding characteristic with both CAS (catalytic active site) and PAS (peripheral anionic site) of AChE, simultaneously. Additionally, this compound also displayed ability to prevent advanced glycation end products formation (IC50 = 23.0 µM) with additional radical scavenging property (IC50 = 37.12 nM). It (7m) also ameliorated scopolamine induced memory deficit in mice employing Morris water maze test. Thus, flavonoids might be the promising lead compounds as potential polyfunctional anti-Alzheimer's agents.
The present study was designed to investigate the role of mast cells and mast cell-derived histam... more The present study was designed to investigate the role of mast cells and mast cell-derived histamine in vincristine-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (100 μg/kg, i.p.) over a period of 10 days, with a break of 2 days, and pain behavioural estimations including pin prick, hot plate and acetone spray tests were performed to assess mechanical and heat hyperalgesia and cold allodynia, respectively, on days 0, 14 and 28. Mast cell stabilizer, sodium cromoglycate, H1 receptor antagonist promethazine and H2 receptor antagonist ranitidine were administered over a period of 12 days. Administration of vincristine resulted in significant development of heat and mechanical hyperalgesia as well as cold allodynia. Furthermore, the pain observed was markedly elevated on the 28th day in comparison to the 14th day. Administration of sodium cromoglycate, promethazine and ranitidine significantly reduced mechanical and heat hyperalgesia and cold allodynia. However, the pain-attenuating effects of ranitidine were significantly less as compared to sodium cromoglycate and promethazine, which suggests that H1 receptors play a more important role than H2 receptors in vincristine-induced neuropathic pain. It may be concluded that vincristine may degranulate mast cells to release inflammatory mediators, particularly histamine which may act through H1 (primarily H1) and H2 receptors to induce neuropathic pain.
Reactive oxygen species are the reactive molecules that are derived from molecular oxygen and pla... more Reactive oxygen species are the reactive molecules that are derived from molecular oxygen and play an important role as redox signaling molecules to confer cardioprotection. Various scientists have demonstrated the key role of redox signaling in cardioprotection by showing a transient increase in their levels during remote ischemic preconditioning (RIPC) phase. The transient increase in reactive oxygen species levels during remote preconditioning phase may take place either through activation of KATP channels or through increased nitric oxide (NO) production. A transient increase in reactive oxygen species during preconditioning may also increase the expression of heat shock proteins (HSP), the level of antioxidant enzymes and decrease the expression of inflammatory genes (Egr-1) during ischemia-reperfusion phase to confer cardioprotection. The present review describes the role of redox signaling in RIPC-induced cardioprotective effect with possible mechanisms.
Mast cells are immunological cells that are diversely distributed in different parts of the body.... more Mast cells are immunological cells that are diversely distributed in different parts of the body. Their role in various pathological conditions such as hypersensitivity, atherosclerosis, pulmonary hypertension, and male infertility has been reported by different scientists. Apart from these, a number of studies have shown their important role in pathogenesis of neuropathic pain of diverse aetiology. They have been found to release active mediators, primarily histamine and serotonin on degranulation in response to different stimuli including chemical, nerve damage, toxin or disease-related conditions. The mast cells stabilizer has shown pain attenuating effects by preventing degranulation of mast cells. Similarly, compound 48/80 (first dose 200 μg/100 g and after 6-h interval, second dose of 500 μg/100 g) caused the degranulation of the accumulated endoneurial histamine and 5-HT antagonists have shown pain relieving effects by attenuating the effects of histamine and serotonin, respe...
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, Jan 3, 2017
The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, i... more The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, in chronic constriction injury-induced neuropathic pain. Chronic Constriction Injury was performed by putting four loose ligatures around the sciatic nerve. Pain was assessed by determining mechanical hyperalgesia, cold allodynia and heat hyperalgesia on 7th and 14th day post surgery. Perampanel (3mg and 6mg/kg, p.o.) was administered 30min before pain assessment test on 14th day post-surgery. CCI led to significant development of pain and peak symptoms were observed on 14th day. Perampanel significantly attenuated CCI-induced mechanical hyperalgesia, cold allodynia and heat hyperalgesia, at different time intervals 30, 60, 90, 120min, with more substantial effect observed at dose of 6mg/kgNaloxone was administered in CCI subjected rats before perampanel treatment to explore the potential role of opioids in anti-nociceptive effects of perampanel. Naloxone decreased the pain attenuating ef...
Journal of cardiovascular pharmacology and therapeutics, 2017
Remote ischemic preconditioning (RIPC) is an innovative treatment strategy that alleviates ischem... more Remote ischemic preconditioning (RIPC) is an innovative treatment strategy that alleviates ischemia-reperfusion injury, whereby short episodes of regional ischemia and reperfusion delivered to remote organs including hind limb, kidney and intestine, and so on provide protection to the heart. The RIPC is known to reduce infarct size, serum levels of cardiac enzymes, and myocardial dysfunction in various animal species as well as in patients. There have been a large number of studies suggesting that the ATP-sensitive potassium channels (KATP channel) play a significant role as a mediator or end effector in RIPC. The present review discusses the role of KATP channels and possible mechanisms in RIPC-induced cardioprotection.
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mecha... more The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.
The present study has been designed to investigate the possible role of histaminergic pathway in ... more The present study has been designed to investigate the possible role of histaminergic pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo). Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 hr was employed to produce I/R induced cerebral injury in NIH mice. iPoCo involving three episodes of carotid artery occlusion and reperfusion of 10 sec each, was instituted immediately after BCAO just before prolonged reperfusion. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water maze (MWM) test. Rota rod test, inclined beam walking test and neurological severity score (NSS) were performed to assess motor in-coordination and sensorimotor abilities. Brain acetylcholine esterase (AChE) activity, brain myeloperoxidase (MPO) activity, brain thiobarbituric acid reactive species (TBARS) and glutathione level (GSH) were also estimated. BCAO produced a significant rise in cerebra...
The genus Ocimum (family Lamiaceae) has been revered for its diverse biological activities. Vario... more The genus Ocimum (family Lamiaceae) has been revered for its diverse biological activities. Various species have been used traditionally to treat CNS disorders and are proven to have neuroprotective effect that is often attributed to their significant antioxidant activity. Ocimum kilimandscharicum (Karpoora Thulasi), a prominent member of this genus is reported to have marked antioxidant activity but its neuroprotective potential has not been explored. Thus, present study was designed to evaluate the cerebroprotective effect of O. kilimandscharicum leaf extract (OKLE) in mice against ischemia reperfusion (I-R) induced brain injury. Bilateral common carotid artery occlusion (BCCAO) for 15min followed by 24h reperfusion was used to induce brain damage in Swiss Albino mice. Animals were treated with OKLE (200 and 400mg/kg, po) once daily for 7days after I-R. Morris water maze and elevated plus maze tests were used to assess long and short term memory while neurological severity score was used to determine motor coordination. Histopathological evaluation (TTC staining) along with brain biochemical parameters (TBARS, reduced GSH and SOD activity) were determined to outline neuroprotective mechanism of OKLE. I-R resulted in marked cognitive impairments, motor incoordination in mice, significant brain damage and increased oxidative stress. Treatment with OKLE produced functional recovery in mice which is manifested by improved memory and motor coordination; reduced cerebral infarct size and brain oxidative stress (TBARS levels) and elevated endogenous antioxidants (reduced GSH and SOD activity). In addition, OKLE showed DPPH radical scavenging and reducing power in-vitro. These results show that O. kilimandscharicum mitigated the neurodegenerative changed induced by I-R in mice probably due to its antioxidant activity.
Chronic pain is broadly classified into somatic, visceral or neuropathic pain depending upon the ... more Chronic pain is broadly classified into somatic, visceral or neuropathic pain depending upon the location and extent of pain perception. Evidences from different animal studies suggest that inflammatory or neuropathic pain is associated with altered acetylation and deacetylation of histone proteins, which result in abnormal transcription of nociceptive processing genes. There have been a number of studies indicating that nerve injury up-regulates histone deacetylase enzymes, which leads to increased histone deacetylation and induce chronic pain. Treatment with histone deacetylase inhibitors relieves pain by normalizing nerve injury-induced down regulation of metabotropic glutamate receptors, glutamate transporters, glutamic acid decarboxylase 65, Neuron restrictive silencer factor and Serum and glucocorticoid inducible kinase 1. On the other hand, a few studies refer to increased expression of histone acetylase enzymes in response to nerve injury that promotes histone acetylation leading to pain induction. Treatment with histone acetyl transferase inhibitors have been reported to relieve chronic pain by blocking the up-regulation of chemokines and cyclooxygenase-2, the critical factors associated with histone acetylation-induced pain. The present review describes the dual role of histone acetylation/deacetylation in development or attenuation of neuropathic pain along with the underlying mechanisms.
There is growing preclinical as well as clinical evidence supporting remote ischemic precondition... more There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoi...
The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but... more The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but its mechanisms still remain to be explored. Therefore, the present study was aimed to explore the possible involvement of 5-lipoxygenase-derived leukotrienes in RIPC. The hind limb was tied by a pressure cuff and was subjected to four episodes of inflation and deflation (5min each) to induce remote hind-limb preconditioning. Thereafter, the hearts were isolated and were subjected to global ischemia (30min) followed by reperfusion (120min) on the Langendorff apparatus. The extent of myocardial injury was assessed by measuring lactate dehydrogenase (LDH) and creatine kinase (CK) levels in the coronary effluent; the infarct size using TTC staining, and the hemodynamic parameters including LVDP, dp/dtmax and dp/dtmin. RIPC significantly decreased ischemia and reperfusion-induced increase in LDH, CK release, infarct size and improved LVDP, dp/dtmax and dp/dtmin. Administration of montelukast...
Memory, one of the most complex functions of the brain comprises of multiple components such as p... more Memory, one of the most complex functions of the brain comprises of multiple components such as perception, registration, consolidation, storage, retrieval and decay. The present study was undertaken to evaluate the impact of different training sessions on the retention capacity of rats. The capacity of retention of learnt task was measured using exteroceptive behavioral models such as Hexagonal swimming pool apparatus, Hebb-Williams maze and Elevated plus-maze. A total of 150 rats divided into fifteen groups were employed in the present study. The animals were subjected to different training sessions during first three days. The ability to retain the learned task was tested after single, sub-acute, acute, sub-chronic and chronic exposure to above exteroceptive memory models in separate groups of animals. The memory score of all animals was recorded after 72 h, 192 h and 432 h of their last training trial. Rats of single exposure group did not show any effect on memory. Sub-acute training group animals showed improved memory up to 72 h only, where as in acute and sub-chronic training groups this memory improvement was extended up to 192 h. The rats, which were subjected to chronic exposures showed a significant improvement in retention capacity that lasted up to a period of eighteen days. These observations suggest that repeated rehearsals at regular intervals are probably necessary for consolidation of long-term memory. It was observed that sub-acute, acute and sub-chronic exposures, improved the retrieval ability of rats but this memory improving effect was short lived. Thus, rehearsal or training plays a crucial role in enhancing one's capacity of retaining the learnt information.
The present study investigated the role of N-methyl-D-aspartate (NMDA) receptors in pioglitazone-... more The present study investigated the role of N-methyl-D-aspartate (NMDA) receptors in pioglitazone-mediated protection against renal ischemia reperfusion injury (IRI) in rats. Male wistar rats were subjected to 40 min of bilateral renal ischemia followed by reperfusion for 24 h to induce kidney injury. The renal damage was evaluated by measuring serum creatinine, creatinine clearance, blood urea nitrogen, uric acid, electrolytes, and microproteinuria in rats. Oxidative stress in renal tissues was quantified in terms of myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione level. Hematoxylin-eosin and periodic acid Schiff staining of renal tissues were performed to observe histological changes. Pioglitazone (20 and 40 mg/kg) was administered 1 h prior to ischemia in rats. In separate groups, NMDA agonists, glutamic acid (200 mg/kg), and spermidine (20 mg/kg) were administered 1 h prior to pioglitazone treatment, followed by renal IRI in rats. Ischemia reperfusion resulted in marked renal damage with significant changes in serum and urine parameters along with marked oxidative stress and histological changes in kidneys. Pioglitazone treatment afforded anti-oxidant effect and renoprotection in a dose-dependent manner in rats. Pioglitazone-mediated renoprotection was attenuated by glutamic acid and spermidine pretreatment in rats, which indicated the role of NMDA receptors in pioglitazone-mediated protection. It is concluded that NMDA antagonism serves as one of the mechanisms in pioglitazone-mediated protection against renal IRI in rats.
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