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Myelin is a spiral compilation of uniformly thick membranes around the axon in an alternating fashion, and it is formed by a complicated process known as myelination. Myelin sheaths are responsible for various physiological functions such as metabolism, rapid nerve conduction, and maintaining ionic and water homeostasis in the brain. Lipid is one of the major components in the myelin, which includes cholesterol, ceramide, and their derivatives, such as galactosylceramide, sulfatide, and gangliosides. Ceramide and its derivatives are synthesised by various ceramide biosynthetic pathways such as de novo, salvage, sphingomyelinase, and recycling of exogenous ceramide. At an appropriate level, ceramide facilitates the development of the nervous system, cell proliferation, autophagy, and apoptosis, which are responsible for normal functioning, but when the level is altered from normal, it results in mitochondrial dysfunction or cell death through autophagy and apoptosis. The ceramide level increases, especially in the mitochondria. Ceramide level increases in response to oxidative stress which is mediated by inflammatory cytokines. Due to mitochondrial dysfunction, an energy-deficient condition is created because of disruption in the electron transport chain, which results in the death of neurons and glial cells, which subsequently cause demyelination and degeneration of axon. Losing myelin while axons remain relatively intact is the characteristic feature of demyelinating diseases. The primary element of demyelinating disorder is damage, malfunction, failure, or death of mitochondria. These disturbances may occur due to direct or indirect interaction of ceramide with mitochondria. There are several risk factors for demyelination, such as viruses, bacteria, fungi, trauma, obesity, vitamin D deficiency, and genetic and environmental factors. Thus, the review is mainly aimed towards the interaction between ceramide and mitochondria during demyelination. [ABSTRACT FROM AUTHOR]

Complicated intra-abdominal infection (cIAI) management involves administering antibiotics that destroy the cell wall and the genesis of bacterial lipopolysaccharide (LPS). During the infectious state, the expression of transferrin receptors upregulates on the intestinal epithelial cells, which are considered the site of infection. In the present research, transferrin decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulated moxifloxacin (MOX) were developed for possible targeting of the receptors in the colon. This study will explore more about the incorporation of transferrin as effective coating material in targeted drug delivery. Nanoparticles were prepared using nano-emulsification and surface modification with transferrin was done by layer-by-layer methodology and evaluated by powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), FTIR, SEM, antibacterial activity, and cellular uptake studies. The formulated NPs exhibit a size of ≈170 nm, PDI ≈ 0.25, zeta potential ≈−4.0 mV, drug loading ≈ 6.8%, and entrapment efficiency of 82%. Transferrin-decorated NPs exhibit tailored release for almost 12 h and in vitro antibacterial activity for 14 h. The cellular uptake studies were done on a RAW264.7 cell line for better determination of transferrin uptake of fabricated NPs. The above study circumvents around the preparation of transferrin decorated PLGA encumbered MOX NPs intended for cIAI-induced sepsis. PLGA NPs provide tailored release of MOX with primary burst and followed by sustained release. These observations confines with antibacterial activity studies. The prepared transferrin-coated NPs were stable and effectively uptaken by RAW264.7 cells. However, future studies include the preclinical investigation of these NPs in sepsis-induced murine models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Manilkara hexandra (Roxb; Family:sapotaceae) is reported to exert preventive effect in several experimental ulcer models. However, there is no report of M. hexandra on gastric ulcer healing property. Thus, the present study was designed to evaluate the gastric ulcer healing activity of methanolic stem bark extract of M. hexandra (MH) and to derive a plausible molecular level of mechanism of action. MH was subjected to several phytochemical screening tests and standardized to quercetin by HPTLC. In the first pharmacological experiment, the standardized MH (50, 100 and 200 mg/kg) was carried out for ulcer healing activity against acetic acid (AA)-induced gastric ulcer in male rats. MH (100 and 200 mg/kg) ameliorated AA-induced rat gastric lesions. Further, MH (100 and 200 mg/kg) attenuated AA-induced changes in the levels of lipid peroxidation (LPO), reduced glutathione (GSH), oxidized glutathione (GSSG) and ratio of GSH/GSSG and activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes, and level of hame oxygenase-1 (HO-1) in stomach tissue. In the subsequent set of experiment, trigonelline (30 mg/kg; p.o.), a potent Nrf2 antagonist, significantly abrogated the gastric ulcer healing activity of MH (100 mg/kg) in AA challenged animals. Further, trigonelline attenuated the effects of MH (100 mg/kg) on the levels of LPO, GSH, GSSG and ratio of GSH/GSSG and activity of SOD, CAT, GPx and GR enzymes, and level of HO-1 in AA challenged rodents. These observations implicate the fact that MH could be a better therapeutic alternative in the management of gastric ulcer. [ABSTRACT FROM AUTHOR]

Background/Aim: Alzheimer’s disease (AD), a type of neurodegenerative disorder, possesses significant memory loss as one of the cardinal manifestations. The pathophysiology of AD includes increased accumulation of Aβ, degeneration of cholinergic activity and mitochondrial dysfunction. Nicotinic acetylcholine receptors (nAChRs) especially alpha7 nicotinic acetylcholine receptors (α7 nAChRs) are widely distributed in brain and associated with memory function. Further, we explored the correlation between the mitochondrial dysfunction and the expression level of α7 nAChRs in STZ challenged brain regions of rats. Materials and Methods: The STZ group rats received intracerebroventricular infusion of STZ (3 mg/kg) on D-1 and D-3 of experimental design of 18 days. Behavioral parameters ware investigated using MWM and Y-maze test paradigm. Further, biochemical analysis was assessed in all three regions of rats. Results: STZ administration caused significant impairment in memory and learning of rats MWM and Y-maze test paradigm. There was significant decrease in level expression of α7 nAChRs and cholinergic functions in terms of elevated AChE activity and decreased ACh level and ChAT activity in rat hippocampus, pre-frontal cortex and amygdala. Further, STZ administration significantly attenuated the mitochondrial function, integrity and bioenergetics in all the selected brain regions. Interestingly, the intracerebroventricular infusion of STZ increased Aβ level in all the rat brain regions. Conclusion: The α7 nAChR down regulation may form a basis to cognitive deficits along with cholinergic dysfunction, Aβ accumulation and mitochondrial dysfunction in memory sensitive rat brain regions. Thus, α7 nAChR could be an alternative and potential target in the management of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment. Adenosinergic receptors are considered as a potential alternative in the management of several neurodegenerative disorders. However, there is no information available on the role of A2b receptor in the pathophysiology of AD. Therefore, the effect of Aβ on the level of expression of A2b receptor was investigated in discrete memory-sensitive mouse brain regions. Aβ (1–42) was injected intracerebroventricularly to healthy male mouse to induce AD-like behavioral manifestations on Day-1 (D-1) of the experimental protocol. The animals were subjected to the Morris water maze (MWM) test on D-14 to D-18. On D-18, the animals were subjected to the Y-maze test after 30 min lag to the MWM paradigm. Aβ significantly attenuated the spatial working memory in MWM and Y-maze tests. In addition, Aβ significantly increased cholinergic dysfunction in terms of decrease in the activity of ChAT and ACh level and increase in the AChE activity in the hippocampus, pre-frontal cortex and amygdala of AD-like animals. Further, there was a significant increase in the extent of apoptosis in the selected mouse brain regions. Moreover, Aβ caused a substantial reduction in the mitochondrial function, integrity and bioenergetics in all the mouse brain regions. Furthermore, there was a significant decrease in the level of expression of A2b receptors in the selected brain regions of the rodents. Hence, it can be assumed that A2b receptor downregulation could be another therapeutic target in the management of AD. [ABSTRACT FROM AUTHOR]

• Ruthenium red (RR) reduced Streptozotocin (STZ)-induced memory loss in male rats. • RR attenuated STZ-induced mitochondrial toxicity in rat HIP, PFC and AMY. • RR reduced STZ-induced increase in mitochondrial calcium level in rat brain. • RR reduced STZ-induced increase in the level of Cytochrome-C in rat brain. • Spermine did not alter STZ-induced mitochondrial toxicity in rat brain. Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal manifestation of cognitive dysfunction. The limitation to avail a successful drug candidate encourages researchers to establish an appropriate animal model in the novel anti-AD drug discovery process. In this context, the mechanism of mitochondrial dysfunction in cognitive deficit animals is yet to be established for intracerebroventricular injection of streptozotocin (ICV-STZ). Experimental dementia was induced in male rats by ICV-STZ on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. ICV-STZ caused cognitive decline in terms of increase in the escape latency on D-14 to D-17 and, decrease in the time spent and percentage of distance travelled in the target quadrant during Morris water maze and decrease in the spontaneous alteration behavior during Y-maze tests in rats. Further, ICV-STZ decreased the level of acetylcholine and activity of choline acetyltransferase and increased the activity of acetylcholinesterase in rat hippocampus, pre-frontal cortex and amygdala. Interestingly, ICV-STZ increased the mitochondrial calcium in addition to decrease in the mitochondrial function, integrity and bioenergetics in all rat brain regions. Further, ICV-STZ enhanced the levels of expression of NR1 subunit of N-methyl-d-aspartate receptor, mitochondrial calcium uniporter and sodium-calcium exchanger in these rat brain regions. Thus, NR1-dependent mitochondrial calcium accumulation could be considered as a major attribute to the animal model of ICV-STZ-induced AD-like manifestations. Further, drugs targeting to manage mitochondrial calcium homeostasis could best be studied in this animal model. [ABSTRACT FROM AUTHOR]

Background: Post-traumatic stress disorder (PTSD) develops after exposure to a severe traumatic event. Stress re-stress (SRS) model of PTSD using forced swim as a re-stress shows hypocortisolism, an index of hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Despite this, the SRS model lacks development of hyperarousal and intrusive memory which are prominent symptoms of PTSD. Aim: Developing a model which shows more clinical similarities to PTSD. We used intense foot-shock (FS) (2 mA for 10 sec) instead of the forced-swim test (FST) as a re-stress cue. Methods: The stress session was performed on D-2 except control group. The FST group rats were forced to swim for 20 min, and FS group rats were exposed to foot shock of 2 mA for 10 sec. The re-stress sessions of FST and FS were performed on D-8, 14, 20, 26 and 32. The freezing behavior was evaluated after the FS re-stress cue, and remaining behavioral assessments such as anxiety and depressive-like behavior, and cognitive dysfunction were performed on last day of the experiment. Results: The FS-induced PTSD-like (anxiety and depressive-like behavior, and cognitive dysfunction) symptoms and a decrease in plasma corticosterone were more significant compared to FST. The hyperarousal and intrusive memory induced by FS were additional symptoms in the SRS model. Treatment with paroxetine significantly attenuated FST and FS-induced behavioral deficits in PTSD rats. Conclusion: FS as a re-stress model shows prominent PTSD-like symptoms with HPA axis dysfunction compared to FST. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic neurodegenerative disorder with clinical symptoms of neuroinflammation and demyelination in the central nervous system. Recently, herbal medicines are clinically effective against MS as the current disease-modifying drugs have limited effectiveness. Hence, the present study evaluated the therapeutic potential of Ocimum basilicum essential oil (OB) in ethidium bromide (EB)-induced cognitive deficits in the male rats. Further, the effect of OB (50, 100 and 200 μL/kg) was evaluated on EB-induced neuroinflammation, astrogliosis and mitochondrial dysfunction in the pre-frontal cortex (PFC) of the animals. The EB was injected through bilateral intracerebroventricular route into hippocampus to induce MS-like manifestations in the rats. OB (100 and 200 μL/kg) and Ursolic acid (UA) significantly reduced the EB-induced cognitive deficits in Morris water maze and Y-maze test paradigms. OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced neuroinflammation in terms of increase in the levels of pro-inflammatory cytokines (TNF-alpha and IL-6) in the rat PFC. Further, OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced astrogliosis in terms of increase in the levels of GFAP (Glial fibrillary acidic protein) and Iba-1 (Ionized calcium binding adaptor molecule-1) in the rat PFC. In addition, OB (100 and 200 μL/kg) and UA significantly attenuated the EB-induced decrease in the mitochondrial function, integrity, respiratory control rate and ADP/O in the PFC of the rodents. Moreover, OB (100 and 200 μL/kg) and UA significantly reduced the EB-induced mitochondria-dependent apoptosis in the PFC of the rat. Hence, it can be presumed that OB could be a potential alternative drug candidate in the pharmacotherapy of MS. [ABSTRACT FROM AUTHOR]

Aim/Background: The level of phosphorylated Estrogen Receptor alpha (ERα) in the nucleus was investigated in different memory-sensitive brain regions of estrogendeficient female rats. Further, the levels of cyclic nucleotides were estimated in those brain regions to draw a possible correlation with phosphorylated ERα signaling. Materials and Methods: Bilateral ovariectomy was performed on the first day of the experimental schedule of 60 days. Behavioural analysis was performed and various biochemical parameters were assessed in discrete brain regions of rat. Results: Ovariectomy caused a significant deterioration in learning and memory of the animals in terms of increase in transfer latency, decrease in time spent and percentage of total distance traveled in the target quadrant in Morris Water Maze (MWM) test protocol. Further, ovariectomy reduced the spontaneous alteration behavior of the rats in the Y-maze test. There was a significant increase in cholinergic dysfunction in respect of decrease in the activity of choline acetyltransferase and level of acetylcholine and an increase in the activity of acetylcholinesterase in rat hippocampus, pre-frontal cortex and amygdala. Subsequently, ovariectomy significantly reduced the extent of phosphorylation and translocation of ERα in such rat brain regions. Moreover, ovariectomy caused a decrease in the levels of cyclic nucleotides such as cAMP and cGMP in these rat brain regions. Additionally, there was a significant positive correlation between the ratio of cyclic nucleotides (cGMP/cAMP) and nuclear p-ERα in all brain regions of these ovariectomized animals. Conclusion: The cyclic nucleotides could be a potential and alternate target to promote the phosphorylated ERα receptor-mediated mechanism during memory formation in estrogen deficiency condition. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, disorientation and gradual deterioration of intellectual ability. In the pharmacotherapy of AD, the mitochondrial protective activity of Exendin-4 in experimental studies is yet to be established though its effectiveness is demonstrated in these patients. Therefore, the mitochondria protective activity of Exendin-4 (5 μg/kg, i.p.) was investigated in hippocampus and pre-frontal cortex (PFC) of AD-like animals. The amyloid beta (Aβ) was injected through bilateral intracerebroventricular route into lateral ventricles to induce AD-like manifestations in the male rats. Exendin-4 significantly attenuated Aβ-induced memory-deficits in the Morris water maze and Y-maze test protocols. Exendin-4 significantly decreased Aβ-induced increase in the level of Aβ in both brain regions. Exendin-4 significantly increased Aβ-induced decrease in acetylcholine level and activity of cholineacetyl transferase in all brain regions. Moreover, Exendin-4 significantly decreased Aβ-induced increase in the activity of acetylcholinestrase in both the brain regions. E4 significantly increased Aβ-induced decrease in mitochondrial function, integrity, respiratory control rate and ADP/O in all brain regions. Further, Exendin-4 significantly decreased Aβ-induced increase in the mitochondrial complex enzyme-I, IV and V activities in all brain regions. Furthermore, Exendin-4 significantly increased Aβ-induced decrease in the level of phosphorylated Akt and the ratio of phosphorylated Akt to Akt in both brain regions. However, LY294002 diminished the therapeutic effects of Exendin-4 on behavioral, biochemical and molecular observations in AD-like animals. Pearson's analysis showed that the attributes of mitochondrial dysfunction (MMP and RCR) exhibited significant correlation to the loss in memory formation, level of Aβ and cholinergic dysfunction in these animals. Thus, it can be speculated that Exendin-4 may mitigate AD-like manifestations including mitochondrial toxicity perhaps through PI3K/Akt-mediated pathway in the experimental animals. Hence, Exendin-4 could be a potential therapeutic alternative candidate in the management of AD. Image 1 • Exendin-4 (E4) reduced memory impairment of amyloid beta (Aβ) challenged rats. • E4 reduced Aβ aggregation in hippocampus and pre-frontal cortex of Aβ treated rats. • E4 reduced cholinergic dysfunction in both the brain regions of Aβ treated rats. • E4 reduced mitochondrial toxicity in both the brain regions of Aβ treated rats. • LY-294002 abrogated the therapeutic effects of E4 in Aβ challenged rats. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Clitoria ternatea flower is traditionally used in the treatment of respiratory disorders including bronchitis and is one of the ingredients in different Ayurvedic preparations that are used in respiratory disorders. However, till date there is no scientific report on the anti-asthmatic activity of this flower. Aim of the study Ethanolic extract of Clitoria ternatea flowers (ECT) was evaluated for its anti-allergy and anti-tussive potential in experimental animals. Additionally, the anti-inflammatory potential of ECT was carried out to draw a plausible mechanism of action of the drug. Materials and Methods In-vitro anti-asthmatic activity of ECT was evaluated in goat tracheal chain and isolated guinea pig ileum preparations. Acute and chronic anti-asthmatic activity of ECT (100, 200 and 400 mg/kg; p.o.) was estimated in histamine aerosol exposed guinea pigs and in OVA sensitized and challenged mice respectively. Anti-tussive activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against sulfur dioxide- and citric acid-induced cough in experimental animals. Moreover, the anti-inflammatory activity of ECT (100, 200 and 400 mg/kg; p.o.) was evaluated against carrageenan- and acetic acid-induced inflammation in rats. Results ECT attenuated histamine-induced contraction in both goat tracheal chain and isolated guinea pig ileum preparations. ECT (400 mg/kg) attenuated histamine-induced dyspnoea and OVA-induced changes in differential cell count in broncheoalveolar fluid, levels of interleukins (IL-1beta and IL-6) and immunoglobulin (OVA-sensitive IgG1) in animals. ECT (400 mg/kg) further ameliorated sulfur dioxide- and citric acid-induced cough in experimental animals. Additionally, ECT (400 mg/kg) attenuated inflammation in carrageenan and acetic acid challenged rodents. Conclusions Standardized ECT could be considered as a potential therapeutic alternative in the management of allergy-induced asthma. [ABSTRACT FROM AUTHOR]

Context:Metformin attenuates type-2 diabetes mellitus (T2DM)-induced hepatic dysfunction and altered PI3K/Akt/GLUT-4 signalling in experimental studies. However, its effect on bicuculline-sensitive gamma amino butyric acid (GABA)-A receptor (GABAAR)-mediated calcium-dependent PI3K/Akt/GLUT-4 signalling in liver challenged to T2DM has not been established. Objective:The effectiveness of metformin on bicuculline-sensitive GABAAR-mediated hepatic insulin signalling was carried out in presence or absence of bicuculline (2.0 mg/kg, i.p.) in experimental T2DM rats. Materials and methods:The whole experimental design was divided into three independent sets of experiments. Each set comprised seven groups of six male rats each. T2DM was induced in the animals by administering streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.) at a time lag of 15 min except control group rats in three experiments. Metformin and/or bicuculline or wortmannin were administered once daily for one week from seventh day of streptozotocin injection in all the experimental sets. Results:Metformin attenuated T2DM-induced hyperglycaemia in glucose (40%) and insulin (50%) tolerance tests in rats. Metformin also attenuated T2DM-induced hyperglycaemia (40%), hyperinsulinaemia (30%), insulin resistance (50%) and β-cell dysfunction (300%) in the animals. Metformin did not attenuate T2DM-induced decrease in rat hepatic intracellular calcium. Further, metformin mitigated T2DM-induced decrease in hepatic phosphorylated Akt and GLUT-4 translocation in the animals. The anti-diabetic activity of metformin was abolished by wortmannin but not with bicuculline co-administration in T2DM animals. Discussion and conclusion:These results suggest that metformin ameliorated T2DM-induced hepatic insulin resistance through bicuculline-sensitive GABAAreceptor-independent PI3K/Akt/GLUT-4 signalling pathway in animals. [ABSTRACT FROM PUBLISHER]

Context: Eugenol, an essential constituent found in plants such as Eugenia caryophyllata Thunb. (Myrtaceae) is reported to possess neuroprotective and anti-stress activities. These activities can potentially be useful in the treatment of stress-induced irritable bowel syndrome (IBS). Objective: The protective effect of eugenol was assessed against restraint stress (RS)-induced IBS-like gastrointestinal dysfunction in rats. Further, its centrally mediated effect was evaluated in this model. Materials and methods: Eugenol (12.5, 25, and 50 mg/kg), ondansetron (4.0 mg/kg, p.o.), and vehicle were administered to rats for 7 consecutive days before exposure to 1 h RS. One control group was not exposed to RS-induction. The effect of eugenol (50 mg/kg) with and without RS exposure was evaluated for mechanism of action and per se effect, respectively. The hypothalamic-pituitary-adrenal cortex (HPA)-axis function was evaluated by estimating the plasma corticosterone level. The levels of brain monoamines, namely serotonin, norepinephrine, dopamine, and their metabolites were estimated in stress-responsive regions such as hippocampus, hypothalamus, pre-frontal cortex (PFC), and amygdala. Oxidative damage and antioxidant defenses were also assessed in brain regions. Results: Eugenol (50 mg/kg) reduced 80% of RS-induced increase in fecal pellets similar to that of ondansetron. Eugenol attenuated 80% of stress-induced increase in plasma corticosterone and modulated the serotonergic system in the PFC and amygdala. Eugenol attenuated stress-induced changes in norepinephrine and potentiated the antioxidant defense system in all brain regions. Conclusion: Eugenol protected against RS-induced development of IBS-like gastrointestinal dysfunction through modulation of HPA-axis and brain monoaminergic pathways apart from its antioxidant effect. [ABSTRACT FROM AUTHOR]

Certain novel 3-aryl/heteroaryl-substituted 2-(2-chlorostyryl)-6,7-dimethoxy-quinazolin-4(3 H)-one ( 5a-5l) derivatives have been synthesized and evaluated for their anticonvulsant activity against maximal electroshock (MES)-, subcutaneous pentylenetetrazole ( scPTZ)- and intracerebroventricular ( icv) AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The acute neurotoxicity was determined using the rotarod test, and hepatotoxicity was also assessed by estimating the AST (alanine aminotransferase) and ALT (alanine aminotransferase) enzyme activity. Among all the synthesized compounds, 5g showed the most significant anticonvulsant activity against MES (ED: 41.3 μmol/kg)-, scPTZ (ED: 82.5 μmol/kg)- and AMPA (ED: 50.3 μmol/kg)-induced seizures with a protective index of 5.1. [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]

Psychological stress is considered as one of the limiting factors in the management of type-2 diabetes mellitus (T2DM). Therefore, the basic objective of the present study was to evaluate the antidiabetic effect of metformin, diazepam, and their combination in cooccurring T2DM and stress condition (DMS). T2DM was induced in the male rats by administering streptozotocin (45mg/kg, i.p.) and nicotinamide (110mg/kg, i.p.) with time lag of 15 min. Rats were subjected to two sessions of cold restraint stress paradigm for one hour on the sixth and seventh day after streptozotocin injection. Administration of metformin (25mg/kg, p.o.) and diazepam (1mg/kg, p.o.) in combination from the seventh to thirteenth day after streptozotocin injection showed better improvement in glucose tolerance and insulin sensitivity compared to monotherapy of either drug. In addition, the combination significantly attenuated DMS-induced hyperglycemia, hypertriglyceridaemia, hypercorticosteronemia, anxiety-like behavior, and insulin resistance through modulating insulin signaling pathway in the liver compared to monotherapy. Further, improvement of mitochondrial function, integrity, and oxidative stress in hippocampus, hypothalamus, prefrontal cortex, striatum, amygdala, and nucleus accumbens was observed with the combination. Therefore, metformin in combination with diazepam may be a better therapeutic option in the management of T2DM with cooccurring stress condition. [ABSTRACT FROM AUTHOR]