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The present study investigated the cardioprotection of Indole-3-carbinol on isoproterenol (ISO)-induced myocardial infarction in Wistar rats. I3C treatment significantly reduced the prolongation of the QRS complex, QT interval, and ST-segment elevation. I3C was also able to normalise blood pressure (SBP, DBP, and MAP) and HR. I3C significantly decreased heart weight, cardiac troponin I (cTn I), CK-MB, LDH, AST and ALT. I3C ameliorated acute hyperglycaemia, hyperlipidemia, and myocardial infarction (%) in ISO rats. I3C treatment significantly elevated the antioxidant enzymes like SOD, CAT, and GSH and attenuated the MDA levels. I3C reduced the inflammatory cytokines (TNF-α and IL-6) and increased the anti-inflammatory cytokine 1 L-10. Furthermore, I3C significantly recovered myocardial structure by inhibiting neutrophil infiltration and oedema. Moreover, I3C attenuated apoptotic markers (cytochrome C, caspase 9 and caspase 3). Consequently, I3C restored cardiac function in MI rats by alleviating oxidative stress, inflammation, and apoptosis, and I3C could be used to treat myocardial infarction. [ABSTRACT FROM AUTHOR]

1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles-Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path. 2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10 mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method. 3. The study observes that CGA is rapidly absorbed in plasma with tmax of 1 min similar to IV route after IN administration. The peak plasma concentration and AUC0-24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route. 4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360 min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUCbrain, IN) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUCbrain, IV) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Following anoxia, a rapid and marked mitochondrial-linked cell death occurs in the cerebral cortex of newborn rats which leads to insult advancement within a couple of days and causes lifelong neurobehavioral abnormalities. The present study investigated the role of 2,4 dinitrophenol (2,4 DNP) in three doses, i.e.,1, 2.5, and 5 mg/kg on anoxia-induced time-dependent mitochondrial dysfunction and associated neurobehavioral outcome using a well-established global model of anoxia. Briefly, rat pups of 30-h age (P2) were subjected to two episodes of anoxia (10 min each) at 24 h of the time interval in an enclosed chamber supplied with 100% N2 and immersed in a water bath (35-37 °C) to avoid hypothermia. Results demonstrated that the uncoupler 2,4 DNP, in the dose 2.5 and 5 mg/kg injected i.p. within 5 min after second anoxic episode significantly (P < 0.05) preserved mitochondrial function on day 7 preferentially by maintaining mitochondrial membrane potential (MMP) and inhibiting mitochondrial permeability transition (MPT) pore. Further, 2,4 DNP preserved mitochondrial function by improving different states of mitochondrial respiration (s2, s3, s4, s5), respiratory control ratio (RCR), antioxidant enzyme system like superoxide dismutase (SOD) and catalase (CAT), and mitochondrial complex enzymes (I, II, IV, V) after anoxia. Furthermore, a marked decrease in the levels of expression of cytochrome C (cyt C) and pro-apoptotic (Bcl-2 family) and apoptotic (caspase-9/3) proteins was observed on day 7 indicating that the treatment with 2,4 DNP prevented mitochondrial dysfunction and further insult progression (day 1 to day 7). Moreover, 2,4 DNP decreased the apoptotic cell death on day 7 and overall improved the neurobehavioral outcomes like reflex latency and hanging latency which suggests its role in treating neonatal anoxia. [ABSTRACT FROM AUTHOR]

Atorvastatin (ATV) generally used to treat dyslipidemia is also reported to have effect against 6-hydroxydopamine (6-OHDA) induced neurotoxicity. Additionally, atorvastatin can interfere with mitochondrial function by reducing the level of Q10. Therefore, the therapeutic effect of atorvastatin (20 mg/kg) could be compromised. In this context, the present study evaluated the effect of ATV supplemented with Q10. 6-OHDA was unilaterally injected into the right striatum of male rats. On day 8 of 6-OHDA infusion, ATV (20 mg/kg), Q10 (200 mg/kg), and their combination were administered per oral for 14 days. On day 21, there was significant loss of striatal dopamine indicating neurotoxicity. The combination of ATV+Q10 showed significant amelioration of dopamine (DA) toxicity compared to individual treatments. Similarly, ATV+Q10 compared to individual treatment significantly decreased the motor deficits induced by 6-OHDA. Further, 6-OHDA induced mitochondrial dysfunction in the substantia nigra pars compacta (SNpc). There was significant decrease in mitochondrial complex enzyme activities and mitochondrial membrane potential (MMP). Treatment with ATV and ATV+Q10 ameliorated mitochondrial dysfunction by increasing complex enzyme activities; however, only ATV+Q10 were able to stabilize MMP and maintained mitochondrial integrity. Moreover, there was significant induction of oxidative stress as observed from increase in lipid peroxidases (LPO) and nitrite (NO), and decrease in super oxide dismutase (SOD). Treatment with ATV+Q10 significantly altered the above effects indicating antioxidant activity. Furthermore, only combination of ATV and Q10 decreased the 6-OHDA induced expression of cytochrome-C, caspase-9 and caspase-3. Therefore, current results provide evidence that supplementation of Q10 with ATV shows synergistic effect in reducing dopamine toxicity. [ABSTRACT FROM AUTHOR]

Asparagus racemosus Linn. (AR) is used worldwide as a medicinal plant. In the present study, the anxiolytic activity of standardized methanolic extract of root of AR (MAR) was evaluated in open-field test (OFT), hole-board, and elevated plus maze (EPM) tests. Rats received oral pretreatment of MAR in the doses of 50, 100, and 200 mg/kg daily for 7 days and then were evaluated for the anxiolytic activity in different animal models. Both MAR (100 and 200 mg/kg) and diazepam (1 mg/kg, p.o.) increased the grooming behavior, number of central squares crossed, and time spent in the central area during OFT. Further, MAR (100 and 200 mg/kg) increased the head-dip and head-dip/sniffing behavior, and decreased sniffing activity in hole-board test. Furthermore, MAR (100 and 200 mg/kg) increased the percentage entries and time spent to open arm in EPM test paradigm. The anxiolytic activity in the experimental models was similar to that of diazepam. MAR (100 and 200 mg/kg) enhanced the level of amygdalar serotonin and norepinephrine. It also increased the expression of 5-HT receptors in the amygdala. In another set of experiment, flumazenil attenuated the anxiolytic effect of minimum effective dose of MAR (100 mg/kg) in OFT, hole-board, and EPM tests, indicating GABA-mediated mechanism. Moreover, the anxiolytic dose of MAR did not show sedative-like effect in OFT and EPM tests compared to diazepam (6 mg/kg, p.o.). Thus, the anxiolytic response of MAR may involve GABA and serotonergic mechanisms. These preclinical data show that AR can be a potential agent for treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

Present study is an attempt to investigate plausible mechanism involved behind antidiabetic activity of standardized Houttuynia cordata Thunb. extract in streptozotocin-induced diabetic rats. The plant is used as a medicinal salad for lowering blood sugar level in North-Eastern parts of India. Oral administration of extract at 200 and 400 mg/kg dose level daily for 21 days showed a significant (P < 0.05) decrease in fasting plasma glucose and also elevated insulin level in streptozotocin-induced diabetic rats. It also significantly reversed all the alterations in biochemical parameters, that is, total lipid profile, blood urea, creatinine, protein, and antioxidant enzymes in liver, pancreas, and adipose tissue of diabetic rats. Furthermore, we have demonstrated that the extract significantly reversed the expression patterns of various glucose homeostatic enzyme genes like GLUT-2, GLUT-4, and caspase-3 levels but did not show any significant effect on PPAR-γ protein expressions. Additionally, the extract positively regulated mitochondrial membrane potential and succinate dehydrogenase (SDH) activity in diabetic rats. The findings justified the antidiabetic effect of H. cordata which is attributed to an upregulation of GLUT-4 and potential antioxidant activity, whichmay play beneficial role in resolving complication associated with diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The management for post-traumatic stress disorder (PTSD) involves chronic administration of drugs. We have modified the stress re-stress (SRS) model to study the effect of chronic administration of risperidone (RIS) after induction of PTSD in rats. On day-1 (D-1) rats underwent training session for elevated-plus maze (EPM) test. On D-2, rats were subjected to stress protocol of 2 h restraint and 20 min forced-swim test (FST) followed by halothane anesthesia. The rats were exposed to re-stress (FST) on D-8 and at six day intervals on D-14, D-20, D-26 and D-32. The rats were treated with RIS (0.01, 0.1 and 1.0 mg/kg; p.o.) and standard drug, paroxetine (PAX; 10.0 mg/kg; p.o.) from D-8 to D-32. RIS (0.1 mg/kg) and PAX ameliorated SRS-induced immobility. RIS in median dose reversed SRS-induced hypocorticosteronemia both in urine and plasma. RIS in median dose improved SRS-induced behavioral perturbations such as memory impairment and anxiety-like behavior in EPM and Y-maze tests. RIS (0.1 mg/kg) reversed SRS-induced increase in amygdalar serotonin level. RIS (0.1 mg/kg) increased the expression of hippocampal MR thereby reversing the SRS-induced decrease in MR/GR ratio. Pearson's analysis of data on D-32 showed that there was significant correlation of plasma corticosterone, amygdalar serotonin and hippocampal ratio of mineralocorticoid (MR)/glucocorticoid receptor (GR) with SRS-induced behavioral abnormalities. Hence, median dose of RIS shows anti-PTSD-like effect in the modified SRS model. PAX had earlier onset of action in ameliorating behavioral effects of PTSD compared to RIS. However, RIS showed anti-PTSD like effect in sub-therapeutic dose. The mode of anti-PTSD action of RIS seems to involve the HPA-axis and serotonergic system, whereas PAX did not show any significant action on these pathways. The effect of repeated treatment of drugs for PTSD can be evaluated using the modified SRS model. [Copyright &y& Elsevier]

Objectives Asparagus racemosus (AR) is classified as an adaptogen, an important medicinal plant and food. Even though AR is widely used as food and nutraceutical, it has only been evaluated in the context of experimental disorders. Hence, the present study was designed to evaluate the effect of standardized methanolic extract of AR (MAR) on experimentally un-manipulated animals to observe the per se effects on stress pathways. Methods MAR (50, 100, and 200 mg/kg, per oral) was administered for 7 days. Lorazepam (0.5 mg/kg, intraperitoneal) was used as a positive control. On the seventh day, plasma was collected for the estimation of corticosterone (CORT) and norepinephrine (NE), and brain was microdissected into hippocampus, hypothalamus (HYP), pre-frontal cortex, amygdala, and nucleus accumbens to estimate tissue level of monoamines (serotonin, dopamine, and NE), their metabolites, and turnover. Results MAR dose-dependently decreased the plasma CORT and NE levels, indicating its effects on the hypothalamic-pituitary-adrenal cortex axis and the sympathetic-noradrenergic system, respectively. MAR increased the levels of all monoamines in the HYP. However, MAR showed region-specific changes in monoamines and their metabolites, and turnover in other brain regions. Discussion MAR showed a physiological modulation of the stress pathways. Interestingly, in most brain regions the change in monoaminergic systems was limited by a ceiling effect at a dose of 100 mg/kg. These observations could explain the traditional use of AR as an adaptogen and a functional food. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate glucose utilization capacity of bioactivity guided fractions of Hybanthus enneaspermus (H. enneaspermus) and Pedalium murex (P. murex) in isolated rat hemidiaphragm. Methods: Dried coarsely powdered plant material was extracted in ethanol using soxhlation technique, further extract was fractionated using solvents of varying polarity. Glucose utilization capacity of bioactivity guided fractions using isolated rat hemidiaphragm was performed in the present study. Results: The entire tested fraction showed increased glucose uptake capacity, and was found to be maximum in case of chloroform fraction of P. murex extract (CHPM) which was quite comparable to standard insulin (P<0.05). Conclusions: In vitro glucose uptake by hemidiaphragm study showed increased utilization of the glucose by hemidiaphragm in the presence of different fractions. From these findings we can conclude that that different fraction of both plant materials had some extra pancreatic mechanism like glucose uptake by peripheral tissues. [Copyright &y& Elsevier]

The present investigation evaluates the anti-stress activity of risperidone (RIS) in the cold restraint stress (CRS) model and related stress pathways. Rats were pretreated with RIS (0.1 and 1.0 mg/kg) for 21 days before subjecting to CRS. Ultra low dose of RIS (ULD; 0.1 mg/kg) in contrast to higher dose (1.0 mg/kg) significantly reduced stress in terms of ulcer index. ULD also reversed stress-induced increase in plasma corticosterone and norepinephrine levels used as markers for the function of hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) respectively. ULD caused dose and brain region (hippocampus, prefrontal cortex and striatum) specific changes to stress-induced perturbations of serotonin, dopamine and its metabolites indicating modulation of brain monoaminergic system (BMS). ULD did not show any extrapyramidal side effects. Thus, the anti-stress effect ULD is probably mediated through the HPA axis, SNS and BMS. The study indicates a potential use of ULD in stress disorders. [ABSTRACT FROM AUTHOR]

Abstract: Neonatal asphyxia is a primary contributor to neonatal mortality and neuro-developmental disorders. It progresses in two distinct phases, as initial primary process and latter as the secondary process. A dynamic relationship exists between excitotoxicity and mitochondrial dysfunction during the progression of asphyxic injury. Study of status of glutamate and mitochondrial function in tandem during primary and secondary processes may give new leads to the treatment of asphyxia. Neonatal asphyxia was induced in rat pups on the day of birth by subjecting them to two episodes (10min each) of anoxia, 24h apart by passing 100% N2 into an enclosed chamber. The NMDA antagonist ketamine (20mg/kg/day) was administered either for 1 day or 7 days after anoxic exposure. Tissue glutamate and nitric oxide were estimated in the cerebral cortex, extra-cortex and cerebellum. The mitochondria from the above brain regions were used for the estimation of malondialdehyde, and activities of superoxide dismutase and succinate dehydrogenase. Mitochondrial membrane potential was evaluated by using Rhodamine dye. Anoxia during the primary process increased glutamate and nitric oxide levels; however the mitochondrial function was unaltered in terms of succinate dehydrogenase and membrane potential. Acute ketamine treatment reversed the increase in both glutamate and nitric oxide levels and partially attenuated mitochondrial function in terms of succinate dehydrogenase activity. The elevated glutamate and nitric oxide levels were maintained during the secondary process but however with concomitant loss of mitochondrial function. Repeated ketamine administration reversed glutamate levels only in the cerebral cortex, where as nitric oxide was decreased in all the brain regions. However, repeated ketamine administration was unable to reverse anoxia-induced mitochondrial dysfunction. The failure of glutamate antagonism in the treatment of asphyxia may be due to persistence of mitochondrial dysfunction. Therefore, additionally targeting mitochondrial function may prove to be therapeutically beneficial in the treatment of asphyxia. [Copyright &y& Elsevier]

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic--pituitary--adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ''U''-shaped dose--response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS. [ABSTRACT FROM AUTHOR]

Background Anoxia leads to a robust generation of reactive oxygen species/nitrogen species which can result in mitochondrial dysfunction and associated cell death in the cerebral cortex of neonates. Aim The present study investigated the pharmacological role of tempol in the treatment of rat neonatal cortical mitochondrial dysfunction induced insult progression (day-1 to day-7) and associated neurobehavioral alterations post-anoxia. Methods Rat pups of 30 h age or postnatal day 2 (PND2) were randomly divided into 5 groups ( n = 5 per group): (1) Control; (2) Anoxia; (3) Anoxia + Tempol 75 mg/kg; (4) Anoxia + Tempol 150 mg/kg; and (5) Anoxia + Tempol 300 mg/kg, and subjected to two episode of anoxia (10 min each) at 24 h of time interval in an enclosed chamber supplied with 100% N 2 . Results Tempol significantly decreased nitric oxide ( NO) formation and simultaneously improved superoxide dismutase (SOD) and catalase (CAT) activities. Further, we observed a significantly ( P < 0.05) improvement in mitochondrial respiration, complex enzyme activities, mitochondrial membrane potential (MMP) along with attenuation of transition pore opening (MPT) after treatment with tempol. Furthermore, tempol decreased expression of mitochondrial Bax, cytochrome-C, caspase-9 and caspase-3 while the increase in expression of cytoplasmic Bax, mitochondrial Bcl-2 on day-7 in cortical region indicating regulation of intrinsic pathway of apoptosis. Further, it improved anoxia-induced neurobehavioral outcome (hanging and reflex latencies). Conclusion Biochemical, molecular and behavioral studies suggest the role of tempol in preserving mitochondrial function and associated neurobehavioral outcomes after neonatal anoxia. [ABSTRACT FROM AUTHOR]

The effects of ELF-PEMF exposure on spontaneous alternation, anxiety, motor coordination, and locomotor activity have been discussed in various pre-clinical and clinical settings. Several epidemiological and experimental studies have demonstrated the potential effects of ELF-PEMF when exposed > ∼1 h/day; however, very few studies have focused on understanding the influence of ELF-PEMF exposure of 1–3 mT with an exposure duration of < 1 h/day on spontaneous alternation, anxiety, motor coordination, and locomotor activity. Hence, we attempted to study the effects of ELF-PEMF exposure of 1–3 mT, 50 Hz with an exposure duration of 20 min each with a 4 h gap (2 times) on the cellular proliferation and morphologies of C6 (Glial) cells and spontaneous alternation, anxiety, motor coordination and locomotor activity of Wistar rats under in vitro and in vivo conditions, respectively. The results showed that ELF-PEMF exposure did not induce any significant levels of cellular fragmentation and changes in the morphology of glial cells. Also, the outcomes revealed no noticeable effects on spontaneous alternation, anxiety, motor coordination, and locomotor activity in PEMF-exposed groups compared with the control. No undesirable side effects were observed at the highest dose (B=3 mT). We also performed histological analysis of the selected brain sections (hippocampus and cortex) following ELF-PEMF exposure. Incidentally, no significant changes were observed in cortical cell counts, tissue structure, and morphology. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Silymarin commonly known for its hepatoprotective effect is reported to show protection against 6-hydroxydopamine-induced neurotoxicity. Silibinin forms the major active constituent of silymarin. Therefore, the neuroprotective effect of silibinin (50, 100 and 200mg/kg) was evaluated in the unilaterally injected 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neurotoxicity in male rats. A battery of tests such as elevated plus maze (EPM), narrow beam walk, open field, bar catalepsy, grip strength, and foot print analysis was performed to evaluate the behavioral symptoms of striatal dopaminergic toxicity. Furthermore, the mechanism of action of silibinin was investigated by evaluating the mitochondrial complex enzyme activities, mitochondrial integrity and oxidative status. Striatal caspase-3 and NFκB were expressed to evaluate the effect of silibinin on apoptosis and inflammation respectively. Silibinin (100 and 200mg/kg) protected against MPP+-induced dopamine depletion in striatum. Silibinin reversed MPP+-induced decrease in transfer latency indicating memory consolidation in the EPM test. Silibinin (100 and 200mg/kg) attenuated MPP+-induced motor deficits, such as fine motor movements and gait. MPP+-induced mitochondrial dysfunction, loss of integrity and oxidative stress were attenuated by silibinin. Silibinin decreased striatal caspase-3 and NFκB expression indicating potential anti-apoptotic and anti-inflammatory effects respectively. Hence, silibinin exhibited neuroprotective effect in the MPP+ induced striatal toxicity augmenting dopamine levels. The mechanism of action may be linked to maintenance of mitochondrial bioenergetics and integrity apart from anti-apoptotic and anti-inflammatory activities. [Copyright &y& Elsevier]

Abstract: Asparagus racemosus Linn. (AR) is an Ayurvedic rasayana used as an adaptogen. Adaptogenic drugs are those which are useful as anti-stress agents by promoting non-specific resistance of the body. Although, the adaptogenic effect of AR is well documented, its use in psychological disorders like depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of methanolic extract of roots of AR (MAR) standardized to saponins (62.2% w/w). Rats were given MAR in the doses of 100, 200 and 400 mg/kg daily for 7 days and then subjected to forced swim test (FST) and learned helplessness test (LH). The results show that MAR decreases immobility in FST and increases avoidance response in LH indicating antidepressant activity. In behavioral experiments, MAR increased the number of head twitches produced by 5-HTP and increased clonidine-induced aggressive behavior indicating facilitatory effect on both serotonergic and adrenergic systems respectively. However, MAR had insignificant effect on l-DOPA-induced aggressive behavior indicating absence of activity on dopaminergic system. MAR also reversed changes to the endogenous antioxidant system induced by FST. Thus, MAR has significant antidepressant activity and this effect is probably mediated through the serotonergic and the noradrenergic systems and augmentation of antioxidant defenses. [Copyright &y& Elsevier]