Modern medicines are gaining less attention due to their limited availability and affordability i... more Modern medicines are gaining less attention due to their limited availability and affordability in human intestinal helminthesis. Thus, most of the world’s population depends to a greater extent on traditional medical remedies. Carissa spinarum, Linn. (Apocynaceae) is a small spinous, evergreen shrub growing throughout India in dry regions. Further, C. spinarum roots are traditionally used for their purgative properties as well as to treat worm infested wounds in animals. There is no report on pharmacologically evaluated antihelmintic activity of root extract of C. spinarum till date. Therefore, in the present study we have investigated the antihelmintic activity of methanolic, aqueous and chloroform extracts of root of C. spinarum on Pheretima posthuma. The fresh and dried root of C. spinarum were collected in the month of November from the Bilaspur region, Chhattisgarh state, India, and the antihelmintic activity was
Argyreia speciosa (AS; Family: Convolvulaceae) is known for its anti-diabetic activity in traditi... more Argyreia speciosa (AS; Family: Convolvulaceae) is known for its anti-diabetic activity in traditional medicine system and is validated in ethnopharmacological studies. However, there is no report till date based on hypoglycemic activity of leave extract of this plant. Hence, the present study explores the anti-hyperglycemic potential of methanolic extract of AS (MAS) in a rat model of type-2 diabetes mellitus (T2DM). T2DM was induced in male rats by a single injection of streptozotocin, 15 min after nicotinamide administration. MAS at highest dose level attenuated the plasma glucose level in rats subjected to glucose load similar to that of metformin. Moreover, both dose of MAS reduced plasma glucose level in normal rats. MAS (400 mg/kg) significantly attenuated the plasma glucose level in T2DM rats. Further, MAS at highest dose level attenuated T2DM-induced increase in the level of total cholesterol, triglyceride and low density lipoprotein, and decrease in the level of high density lipoprotein in the plasma of the rats. MAS (400 mg/kg) attenuated the T2DM-induced increase in the level of lipid peroxidation and decrease in the activities of superoxide dismutase and catalase in both plasma and liver tissues. In addition, MAS at highest dose level improved the T2DM-induced decrease in the level of expression of GLUT-4 in the liver. These results collectively indicate that the anti-hyperglycemic activity of MAS against T2DM condition could be due to the improvement in the aberrant lipid profile, oxidative stress and insulin sensitivity. Hence, MSG could be a potential therapeutic option in the management of T2DM.
Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally use... more Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally used as a nootropic agent. BM also exhibits significant analgesic activity in experimental models of pain. However, the effect of Bacopa monnieri against glutamate-induced nociception in zebrafish is yet to be explored in experimental condition. Therefore, the present study was designed to evaluate the effect of BM against glutamate-induced nociception and brain mitochondrial toxicity in adult zebrafish (Danio rerio). BM at 0.625, 1.25 and 2.5 mg/ml was administered to adult zebrafish and after half an hour glutamate was injected through i.m. route of administration. Indomethacin was used as standard drug. After behavioral analysis, the fish were euthanized and the brain was isolated and stored for further biochemical analysis. BM (1.25 and 2.5 mg/ml) and indomethacin significantly attenuated the glutamate-induced increase in number of line crossing compared to control group animals. Additionally, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate induced increase in cytosolic calcium level. Further, there was a substantial improvement in mitochondrial function, integrity and bioenergetics in term of respiratory control rate and ADP/O in zebrafish brain. Moreover, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate-induced mitochondria-dependent apoptosis in zebrafish brain. Therefore, BM could be a potential alternative drug candidate in the management of pain.
: Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder trig-... more : Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder trig-gered due to the loss of dopamine-releasing neurons in the region of substantia nigra pars compacta characterized by the motor symptoms, such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations are the hallmarks of Parkinson's disease. The bioactive components of Brahmi, such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuropro-tective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mito-chondrial dysfunction, inflammation, inhibition of α-synuclein aggregation, and improvement of cog-nitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress and neuroinflammation and enhance dopamine levels. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD.
Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart... more Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aβ42-induced memory impairment. Aβ42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aβ42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aβ42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aβ42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aβ42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aβ42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aβ42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aβ42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD.
Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an indivi... more Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1-7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1-7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ(1-42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1-7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1-7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1-7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1-7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1-7) could be a potential therapeutic option in the pharmacotherapy of AD.
The objective of present study is to design a novel enteric-coated colon targeting drug delivery ... more The objective of present study is to design a novel enteric-coated colon targeting drug delivery system of 5-fluorouracil (5-FU) using biodegradable guar gum as a carrier for colorectal cancer treatment. Formulation matrix containing 30% guar gum was prepared and coating was done using polymers of hydroxyl propyl methyl cellulose (HPMC) for inner hydrophilic coating and EudragitAL/S-100 for outer enteric coating in different ratio (2:4, 3:2, 3:4 and 4:3). The prepared formulations were subjected to in-vitro drug release studies in various simulated gastric and intestinal fluids, were found gastro resistant for 2 h at pH 1.2 and further 3 hr at pH 7.4, since they released only less than 10% of drug. Furthermore, the release studies was carried out in absence (control) and presence of simulated colonic fluid media containing 2 and 4% w/v rat caecal content. The results obtained after enzyme induction for the period of 2, 4 and 6 days revealed significant release profile compared to c...
The present study extensively investigated the colon as an effective drug delivery site for local... more The present study extensively investigated the colon as an effective drug delivery site for local colorectal cancer treatment using 5-Fluorouracil (5-FU) as model drug based on oral pulsatile release technology. Formulations coated with enteric Eudragit-S100 (EdâS-100) and swellable hydroxyl propyl methyl cellulose (HPMC) to a varying coat thickness of 2:4, 4:2, 3:4 and 4:3, were tested for in-vitro drug dissolution with various simulated fluids of stomach (pH 1.2), small intestine (pH 7.2) and colon (pH 6.8). Guar gum was used as matrix vehicle aimed to delay drug dissolutions and localize in the distal portions of small bowl or colon. The formulation was capable in delaying onset of drug dissolution for a programmed lag time period of 3-5 h in the hostile environment of upper gastrointestinal tract. The optimized enteric coated formulations containing 30% guar gum released only 5-12% approximately of 5-FU during 5 h dissolution studies in hostile physiological environment of stoma...
The present investigation was carried out to focus on the hypoglycemic effect of newly developed ... more The present investigation was carried out to focus on the hypoglycemic effect of newly developed polyherbal formulation (5EPHF) consisting of five medicinal plant extracts viz., Aegel marmelos, Murraya koenigii, Aloe vera, Pongamia pinnata and Elaeodendron glaucum in normal and alloxan induced diabetic rats. The formulation was subjected to pharmacognostic, physico-chemical and phytochemical evaluations which will assist in standardization for authenticity, quality and identification of the herbal products. Further, the results showed that the formulation treated group significantly altered the glucose level in normoglycemic and experimentally-induced diabetic animals. Treatment with 5EPHF at dose 200 mg/kg to diabetic rats resulted in significant reduction of serum glucose, glycosylated haemoglobin, total cholesterol, triglyseride, low density lipoprotein, creatinine, urea whereas significant increased level of insulin and high density lipoprotein was observed. The formulation trea...
The fluctuation in plasma estrogen level influences the cognitive function in the females. The sp... more The fluctuation in plasma estrogen level influences the cognitive function in the females. The specific estrogen receptor alpha (ERα) agonist, (4,4',4″-(4-propyl-[1 H] pyrazole-1,3,5-triyl) tris phenol (PPT), is reported to exhibit therapeutic activity similar to that of estrogen replacement therapy. However, the former can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. Moreover, there is no report of cGMP on ERα-mediated phosphorylation of Akt in the experimental condition. Vinpocetine increases the rate of formation of cGMP than cAMP in several tissues. Hence, the present study evaluated the neuroprotective effect of vinpocetine with or without PPT against ovariectomy-induced dementia in experimental rodents. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Vinpocetine (20 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioral tests and increase in body weight in the rodents. Vinpocetine and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the ovariectomized animals. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in all brain regions was attenuated with the monotherapy of either vinpocetine or PPT. Interestingly, the combination of vinpocetine and PPT exhibited better effectiveness than their monotherapy. However, vinpocetine attenuated the PPT-induced increased level of phosphorylated Akt in discrete brain regions and weight of uterus of these rodents. Hence, the combination could be considered as a better alternative candidate with minimal side effects in the management of estrogen insufficiency-induced disorders.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as o... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aβ-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aβ-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aβ-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aβ 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aβ-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aβ-induced Aβ accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aβ-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.
Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4... more Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.
Neurodegenerative disorders have been considered as a growing health concern for decades. Increas... more Neurodegenerative disorders have been considered as a growing health concern for decades. Increasing risk of neurodegenerative disorders creates a socioeconomic burden to both patients and care givers. Mitochondria are organelle that are involved in both neuroinflammation and neurodegeneration. There are few reports on the effect of mitochondrial metabolism on the progress of neurodegeneration and neuroinflammation. Therefore, the present review summarizes the potential contribution of mitochondrial metabolic pathways in the pathogenesis of neuroinflammation and neurodegeneration. Mitochondrial pyruvate metabolism plays a critical role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. However, there its potential contribution in other neurodegenerative disorders is as yet unproven. The mitochondrial pyruvate carrier and pyruvate dehydrogenase can modulate mitochondrial pyruvate metabolism to attenuate neuroinflammation and neurodegeneration. Further, it has been observed that the mitochondrial citric acid cycle can regulate the pathogenesis of neuroinflammation and neurodegeneration. Additional research should be undertaken to target tricarboxylic acid cycle enzymes to minimize the progress of neuroinflammation and neurodegeneration. It has also been observed that the mitochondrial urea cycle can potentially contribute to the progression of neurodegenerative disorders. Therefore, targeting this pathway may control the mitochondrial dysfunction-induced neuroinflammation and neurodegeneration. Furthermore, the mitochondrial malate-aspartate shuttle could be another target to control mitochondrial dysfunction-induced neuroinflammation and neurodegeneration in neurodegenerative disorders.
Modern medicines are gaining less attention due to their limited availability and affordability i... more Modern medicines are gaining less attention due to their limited availability and affordability in human intestinal helminthesis. Thus, most of the world’s population depends to a greater extent on traditional medical remedies. Carissa spinarum, Linn. (Apocynaceae) is a small spinous, evergreen shrub growing throughout India in dry regions. Further, C. spinarum roots are traditionally used for their purgative properties as well as to treat worm infested wounds in animals. There is no report on pharmacologically evaluated antihelmintic activity of root extract of C. spinarum till date. Therefore, in the present study we have investigated the antihelmintic activity of methanolic, aqueous and chloroform extracts of root of C. spinarum on Pheretima posthuma. The fresh and dried root of C. spinarum were collected in the month of November from the Bilaspur region, Chhattisgarh state, India, and the antihelmintic activity was
Argyreia speciosa (AS; Family: Convolvulaceae) is known for its anti-diabetic activity in traditi... more Argyreia speciosa (AS; Family: Convolvulaceae) is known for its anti-diabetic activity in traditional medicine system and is validated in ethnopharmacological studies. However, there is no report till date based on hypoglycemic activity of leave extract of this plant. Hence, the present study explores the anti-hyperglycemic potential of methanolic extract of AS (MAS) in a rat model of type-2 diabetes mellitus (T2DM). T2DM was induced in male rats by a single injection of streptozotocin, 15 min after nicotinamide administration. MAS at highest dose level attenuated the plasma glucose level in rats subjected to glucose load similar to that of metformin. Moreover, both dose of MAS reduced plasma glucose level in normal rats. MAS (400 mg/kg) significantly attenuated the plasma glucose level in T2DM rats. Further, MAS at highest dose level attenuated T2DM-induced increase in the level of total cholesterol, triglyceride and low density lipoprotein, and decrease in the level of high density lipoprotein in the plasma of the rats. MAS (400 mg/kg) attenuated the T2DM-induced increase in the level of lipid peroxidation and decrease in the activities of superoxide dismutase and catalase in both plasma and liver tissues. In addition, MAS at highest dose level improved the T2DM-induced decrease in the level of expression of GLUT-4 in the liver. These results collectively indicate that the anti-hyperglycemic activity of MAS against T2DM condition could be due to the improvement in the aberrant lipid profile, oxidative stress and insulin sensitivity. Hence, MSG could be a potential therapeutic option in the management of T2DM.
Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally use... more Bacopa monnieri L. (BM; Family: Scrophulariaceae), commonly known as Brahmi, is traditionally used as a nootropic agent. BM also exhibits significant analgesic activity in experimental models of pain. However, the effect of Bacopa monnieri against glutamate-induced nociception in zebrafish is yet to be explored in experimental condition. Therefore, the present study was designed to evaluate the effect of BM against glutamate-induced nociception and brain mitochondrial toxicity in adult zebrafish (Danio rerio). BM at 0.625, 1.25 and 2.5 mg/ml was administered to adult zebrafish and after half an hour glutamate was injected through i.m. route of administration. Indomethacin was used as standard drug. After behavioral analysis, the fish were euthanized and the brain was isolated and stored for further biochemical analysis. BM (1.25 and 2.5 mg/ml) and indomethacin significantly attenuated the glutamate-induced increase in number of line crossing compared to control group animals. Additionally, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate induced increase in cytosolic calcium level. Further, there was a substantial improvement in mitochondrial function, integrity and bioenergetics in term of respiratory control rate and ADP/O in zebrafish brain. Moreover, BM (1.25 and 2.5 mg/ml) and indomethacin significantly reduced the glutamate-induced mitochondria-dependent apoptosis in zebrafish brain. Therefore, BM could be a potential alternative drug candidate in the management of pain.
: Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder trig-... more : Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder trig-gered due to the loss of dopamine-releasing neurons in the region of substantia nigra pars compacta characterized by the motor symptoms, such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations are the hallmarks of Parkinson's disease. The bioactive components of Brahmi, such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuropro-tective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mito-chondrial dysfunction, inflammation, inhibition of α-synuclein aggregation, and improvement of cog-nitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress and neuroinflammation and enhance dopamine levels. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD.
Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart... more Renin Angiotensin System plays significant role in the memory acquisition and consolidation apart from its hemodynamic function in the pathophysiology of Alzheimer's disease (AD). It has been reported that Ang (1-7) ameliorates the cognitive impairment in experimental animals. However, the effect of Ang (1-7)/Mas receptor signaling is yet to be explored in Aβ42-induced memory impairment. Aβ42 was intracerebroventricularly injected into the male rats on day-1 (D-1) of the experimental schedule of 14 days. All the drugs were administered from D-1 to D-14 in the study design. Aβ42 significantly increased the escape latency during Morris water maze (MWM) test on D-10 to13 in the animals. Further, Aβ42 significantly decreased the time spent and percentage of total distance travelled in the target quadrant of the rats on D-14 in the MWM test. Aβ42 also significantly decreased the spontaneous alteration behavior on D-14 during Y-maze test. Moreover, there was a significant increase in the level of Aβ42, decrease in the cholinergic function (in terms of decreased acetylcholine and activity of cholinesterase, and increased activity of acetylcholinesterase), mitochondrial function, integrity and bioenergetics, and apoptosis in all the rat brain regions. Further, Aβ42 significantly decreased the level of expression of heme oxygenase-1 in all the rat brain regions. Ang (1-7) attenuated Aβ42-induced changes in the behavioral, biochemical and molecular observations in all the selected rat brain regions. However, A779, Mas receptor blocker, significantly abolished the beneficial effects of Ang (1-7) in Aβ42-induced cognitive deficit animals. These observations clearly indicate that the Ang (1-7)/Mas receptor activation could be a potential alternative option in the management of AD.
Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an indivi... more Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1-7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1-7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ(1-42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1-7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1-7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1-7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1-7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1-7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1-7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1-7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1-7) could be a potential therapeutic option in the pharmacotherapy of AD.
The objective of present study is to design a novel enteric-coated colon targeting drug delivery ... more The objective of present study is to design a novel enteric-coated colon targeting drug delivery system of 5-fluorouracil (5-FU) using biodegradable guar gum as a carrier for colorectal cancer treatment. Formulation matrix containing 30% guar gum was prepared and coating was done using polymers of hydroxyl propyl methyl cellulose (HPMC) for inner hydrophilic coating and EudragitAL/S-100 for outer enteric coating in different ratio (2:4, 3:2, 3:4 and 4:3). The prepared formulations were subjected to in-vitro drug release studies in various simulated gastric and intestinal fluids, were found gastro resistant for 2 h at pH 1.2 and further 3 hr at pH 7.4, since they released only less than 10% of drug. Furthermore, the release studies was carried out in absence (control) and presence of simulated colonic fluid media containing 2 and 4% w/v rat caecal content. The results obtained after enzyme induction for the period of 2, 4 and 6 days revealed significant release profile compared to c...
The present study extensively investigated the colon as an effective drug delivery site for local... more The present study extensively investigated the colon as an effective drug delivery site for local colorectal cancer treatment using 5-Fluorouracil (5-FU) as model drug based on oral pulsatile release technology. Formulations coated with enteric Eudragit-S100 (EdâS-100) and swellable hydroxyl propyl methyl cellulose (HPMC) to a varying coat thickness of 2:4, 4:2, 3:4 and 4:3, were tested for in-vitro drug dissolution with various simulated fluids of stomach (pH 1.2), small intestine (pH 7.2) and colon (pH 6.8). Guar gum was used as matrix vehicle aimed to delay drug dissolutions and localize in the distal portions of small bowl or colon. The formulation was capable in delaying onset of drug dissolution for a programmed lag time period of 3-5 h in the hostile environment of upper gastrointestinal tract. The optimized enteric coated formulations containing 30% guar gum released only 5-12% approximately of 5-FU during 5 h dissolution studies in hostile physiological environment of stoma...
The present investigation was carried out to focus on the hypoglycemic effect of newly developed ... more The present investigation was carried out to focus on the hypoglycemic effect of newly developed polyherbal formulation (5EPHF) consisting of five medicinal plant extracts viz., Aegel marmelos, Murraya koenigii, Aloe vera, Pongamia pinnata and Elaeodendron glaucum in normal and alloxan induced diabetic rats. The formulation was subjected to pharmacognostic, physico-chemical and phytochemical evaluations which will assist in standardization for authenticity, quality and identification of the herbal products. Further, the results showed that the formulation treated group significantly altered the glucose level in normoglycemic and experimentally-induced diabetic animals. Treatment with 5EPHF at dose 200 mg/kg to diabetic rats resulted in significant reduction of serum glucose, glycosylated haemoglobin, total cholesterol, triglyseride, low density lipoprotein, creatinine, urea whereas significant increased level of insulin and high density lipoprotein was observed. The formulation trea...
The fluctuation in plasma estrogen level influences the cognitive function in the females. The sp... more The fluctuation in plasma estrogen level influences the cognitive function in the females. The specific estrogen receptor alpha (ERα) agonist, (4,4',4″-(4-propyl-[1 H] pyrazole-1,3,5-triyl) tris phenol (PPT), is reported to exhibit therapeutic activity similar to that of estrogen replacement therapy. However, the former can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. Moreover, there is no report of cGMP on ERα-mediated phosphorylation of Akt in the experimental condition. Vinpocetine increases the rate of formation of cGMP than cAMP in several tissues. Hence, the present study evaluated the neuroprotective effect of vinpocetine with or without PPT against ovariectomy-induced dementia in experimental rodents. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Vinpocetine (20 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioral tests and increase in body weight in the rodents. Vinpocetine and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the ovariectomized animals. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in all brain regions was attenuated with the monotherapy of either vinpocetine or PPT. Interestingly, the combination of vinpocetine and PPT exhibited better effectiveness than their monotherapy. However, vinpocetine attenuated the PPT-induced increased level of phosphorylated Akt in discrete brain regions and weight of uterus of these rodents. Hence, the combination could be considered as a better alternative candidate with minimal side effects in the management of estrogen insufficiency-induced disorders.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as o... more Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aβ-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aβ-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aβ-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aβ 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aβ-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aβ-induced Aβ accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aβ-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.
Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4... more Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.
Neurodegenerative disorders have been considered as a growing health concern for decades. Increas... more Neurodegenerative disorders have been considered as a growing health concern for decades. Increasing risk of neurodegenerative disorders creates a socioeconomic burden to both patients and care givers. Mitochondria are organelle that are involved in both neuroinflammation and neurodegeneration. There are few reports on the effect of mitochondrial metabolism on the progress of neurodegeneration and neuroinflammation. Therefore, the present review summarizes the potential contribution of mitochondrial metabolic pathways in the pathogenesis of neuroinflammation and neurodegeneration. Mitochondrial pyruvate metabolism plays a critical role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. However, there its potential contribution in other neurodegenerative disorders is as yet unproven. The mitochondrial pyruvate carrier and pyruvate dehydrogenase can modulate mitochondrial pyruvate metabolism to attenuate neuroinflammation and neurodegeneration. Further, it has been observed that the mitochondrial citric acid cycle can regulate the pathogenesis of neuroinflammation and neurodegeneration. Additional research should be undertaken to target tricarboxylic acid cycle enzymes to minimize the progress of neuroinflammation and neurodegeneration. It has also been observed that the mitochondrial urea cycle can potentially contribute to the progression of neurodegenerative disorders. Therefore, targeting this pathway may control the mitochondrial dysfunction-induced neuroinflammation and neurodegeneration. Furthermore, the mitochondrial malate-aspartate shuttle could be another target to control mitochondrial dysfunction-induced neuroinflammation and neurodegeneration in neurodegenerative disorders.
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