Targeting E. coli invasion of the blood-brain barrier for investigating the pathogenesis and therapeutic development of E. coli meningitis.

Escherichia coli is the most common Gram-negative bacillary organism causing neonatal meningitis. Escherichia coli meningitis remains an important cause of mortality and morbidity, but the pathogenesis of E. coli penetration of the blood-brain barrier remains incompletely understood. Escherichia coli entry into the brain occurs in the meningeal and cortex capillaries, not in the choroid plexus, and exploits epidermal growth factor receptor (EGFR) and cysteinyl leukotrienes (CysLTs) for invasion of the blood-brain barrier. The present study examined whether EGFR and CysLTs are inter-related in their contribution to E. coli invasion of the blood-brain barrier and whether counteracting EGFR and CysLTs is a beneficial adjunct to antibiotic therapy of E. coli meningitis. We showed that (a) meningitis isolates of E. coli exploit EGFR and CysLTs for invasion of the blood-brain barrier, (b) the contribution of EGFR is upstream of that of CysLTs, and (c) counteracting EGFR and CysLTs as an adjunctive therapy improved the outcome (survival, neuronal injury and memory impairment) of animals with E. coli meningitis. These findings suggest that investigation of host factors contributing to E. coli invasion of the blood-brain barrier will help in enhancing the pathogenesis and development of new therapeutic targets for E. coli meningitis in the era of increasing resistance to conventional antibiotics.

Ceftriaxone attenuates glutamate-mediated neuro-inflammation and restores BDNF in MPTP model of Parkinson's disease in rats.

The present study is designed to investigate the role of glutamate transporter in neuroprotection of ceftriaxone against MPTP induced PD animal model. Young male Wistar rats were subjected to intra-nigral administration of MPTP for the induction of Parkinson's disease. Glutamate modulators like ceftriaxone (CFX), Memantine (MEM) and Dihydrokainate (DHK) were administered to MPTP-lesioned rats. Different behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and different biochemical parameters were measured. Intranigral administration of MPTP showed significant impairment of motor behavior and marked increase in inflammatory mediators and oxidative stress parameters in rats. In addition, MPTP also produced significant decrease in brain-derived neurotrophic factor (BDNF) in striatum of rats. However, chronic administration of ceftriaxone (200mg/kg) has shown significant improvement in motor behavioral deficits and oxidative damage. In addition, Ceftriaxone also attenuated the marked increase of NFκB, TNF-α and IL-1ß in MPTP treated rats thus, conferring its neuro-inflammatory property. Further, Ceftriaxone significantly restored the decreased activity of BDNF in striatum of MPTP treated rats. Moreover, pre-treatment of memantine (20mg/kg) with sub-therapeutic dose of ceftriaxone (100mg/kg) potentiated the protective effect of ceftriaxone. Furthermore, intra-nigral injection of DHK (200 nmol) with lower dose of ceftriaxone (100mg/kg) reversed the protective effect of ceftriaxone in MPTP treated rats. The present study concluded that ceftriaxone produce beneficial effect against MPTP induced PD like symptoms rats through glutamatergic pathways.

Brain biometals and Alzheimer's disease - boon or bane?

Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. A complicated array of molecular events has been implicated in the pathogenesis of AD. It is attributed to a variety of pathological conditions that share similar critical processes, such as oxidative stress, proteinaceous aggregations, mitochondrial dysfunctions and energy failure. There is increasing evidence suggesting that metal homeostasis is dysregulated in the pathology of AD. Biometals play an important role in the normal body functioning but AD may be mediated or triggered by disproportion of metal ions leading to changes in critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. The link is multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper (Cu) and other trace metals. Their levels in the brain are found to be elevated in AD. In other neurodegenerative disorders, Cu, zinc, aluminum and manganese are involved. This paper is a review of recent advances of the role of metals in the pathogenesis and pathophysiology of AD and related neurodegenerative diseases.

Possible role of metal ionophore against zinc induced cognitive dysfunction in D-galactose senescent mice.

Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid ß (Aß) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-ß. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of APP in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.

Neuroprotective potential of antioxidant potent fractions from Convolvulus pluricaulis Chois. in 3-nitropropionic acid challenged rats.

OBJECTIVE: To isolate the neuroprotective component from Convolvulus pluricaulis Chois. (Convolvulaceae) which can be used as a lead molecule in the treatment of Huntington's disease (HD). METHODS: The methanolic extract of whole plant was fractionated into four fractions; chloroform, ethyl acetate, n-butanol, and aqueous fraction. The chloroform and ethyl acetate fractions were pooled on the basis of antioxidant activity and TLC profile and charged into silica gel column. Four subfractions were collected from column (FrA, FrB, FrC, and FrD) and further assessed for antioxidant potential by 2,2-diphenyl-1-picrylhydrazyl in vitro assay. 3-Nitropropionic acid (3-NP) was administered to Wister rats for induction of HD. Different fractions were administered for 14 days. Different behavioral alterations were assessed in between study period. Animals were euthanized immediately following the last behavioral session, and biochemical parameters were measured. RESULT AND DISCUSSION: Systemic administration of 3-NP showed marked motor deficits and oxidative damage in rats. Only FrB showed significant antioxidant activity and on further purification gave pure compound (scopoletin). Our study showed that FrB (20 mg/kg) pre-treatment significantly attenuated the loss in body weight, improved the locomotor activity, grip strength, and gait abnormalities. It also has attenuated the increased malondialdehyde and nitrite levels, and restored superoxide dismutase and reduced GSH enzyme activity in the striatum and cortex in 3-NP-treated groups. These results suggest that C. pluricaulis Chois. exhibits a neuroprotective effect by accelerating brain antioxidant defense mechanisms in 3-NP-treated rats.

The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides.

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.

Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity.

Organophosphates (OP) are highly toxic compounds that cause cholinergic neuronal excitotoxicity and dysfunction by irreversible inhibition of acetylcholinesterase, resulting in delayed brain damage. This delayed secondary neuronal destruction, which arises primarily in the cholinergic areas of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, could be largely responsible for persistent profound neuropsychiatric and neurological impairments such as memory, cognitive, mental, emotional, motor, and sensory deficits in the victims of OP poisoning. The therapeutic strategies for reducing neuronal brain damage must adopt a multifunctional approach to the various steps of brain deterioration: (i) standard treatment with atropine and related anticholinergic compounds; (ii) anti-excitotoxic therapies to prevent cerebral edema, blockage of calcium influx, inhibition of apoptosis, and allow for the control of seizure; (iii) neuroprotection by aid of antioxidants and N-methyl-d-aspartate (NMDA) antagonists (multifunctional drug therapy), to inhibit/limit the secondary neuronal damage; and (iv) therapies targeting chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may prevent secondary neuronal damage in both early and late stages of OP poisoning, and thus may be a beneficial approach to treating the neuropsychological and neuronal impairments resulting from OP toxicity.

Mitoprotective effect of Centella asiatica against aluminum-induced neurotoxicity in rats: possible relevance to its anti-oxidant and anti-apoptosis mechanism.

Role of mitochondrial dysfunction and oxidative stress has been well documented in various cognitive-related disorders such as Alzheimer's disease. Aluminum is a neurotoxic metal that may be involved in the progression of neurodegenerative processes. The antioxidant and memory enhancing effects of Centella asiatica (CA) are well known in the last few decades. Therefore, the present study has been designed to explore the neuroprotective effect of CA on chronic aluminum exposure induced mitochondrial enzyme alteration, oxidative stress, apoptosis and cognitive dysfunction in rat. Aluminum (100 mg/kg) and CA (150 and 300 mg/kg) were administered daily for a period of 6 weeks in male Wistar rats. Various behavioral, biochemical and cellular estimations and aluminum concentration were assessed. Chronic aluminum administration resulted in memory impairment and caused marked oxidative damage associated with mitochondria impairment. It also caused a significant increase in caspase-3 activity, acetylcholine esterase activity and aluminum concentration in hippocampus and cerebral cortex of rat brain. Chronic administration of CA significantly improved memory performance, oxidative defense decreased aluminum concentration, caspase-3, acetylcholinestrease activity and reversal of mitochondrial enzyme activity as compared to aluminum-treated animals. Results of the study demonstrate neuroprotective potential of CA against aluminum-induced cognitive dysfunction and mito- oxidative damage.

Pioglitazone alleviates the mitochondrial apoptotic pathway and mito-oxidative damage in the d-galactose-induced mouse model.

Chronic injection of d-galactose can cause gradual deterioration in learning and memory capacity, and activates oxidative stress, mitochondrial dysfunction and apoptotic cell death in the brain of mice. Thus, it serves as an animal model of ageing. Recent evidence has shown that mild cognitive impairment in humans might be alleviated by treatment with piogliatzone (peroxisome proliferator-activated receptor gamma (PPARγ) agonists). To continue exploring the effects of piogliatzone in this model, we focused on behavioural alteration, oxidative damage, mitochondrial dysfunction and apoptosis in d-galactose-induced mice. The ageing model was established by administration of d-galactose (100 mg/kg) for 6 weeks. Pioglitazone (10 and 30 mg/kg) and bisphenol A diglycidyl ether (15 mg/kg) were given daily to d-galactose-induced senescent mice. The cognitive behaviour of mice was monitored using the Morris water maze. The anti-oxidant status and apoptotic activity in the ageing mice was measured by determining mito-oxidative parameters and caspase-3 activity in brain tissue. Systemic administration of d-galactose significantly increased behavioural alterations, biochemical parameters, mitochondrial enzymes, and activations of caspase-3 and acetylcholinesterase enzyme activity as compared with the control group. Piogliatzone treatment significantly improved behavioural abnormalities, biochemical, cellular alterations, and attenuated the caspase-3 and acetylcholinesterase enzyme activity as compared with the control. Furthermore, pretreatment of BADGE (PPARγ antagonist) with pioglitazone reversed the protective effect of pioglitazone in d-galactose-induced mice. The present study highlights the protective effects of pioglitzone against d-galactose-induced memory dysfunction, mito-oxidative damage and apoptosis through activation of PPARγ receptors. These findings suggest that pioglitazone might be helpful for the prevention or alleviation of ageing.

Naringin protects memory impairment and mitochondrial oxidative damage against aluminum-induced neurotoxicity in rats.

Aluminum has been indicated in neurodegenerative disorders and naringin, a bioflavonoid has been used to reduce neurotoxic effects of aluminum against aluminum chloride-induced rats. Therefore, present study has been designed to explore the possible role of naringin against aluminum-induced cognitive dysfunction and oxidative damage in rats. Aluminum (100 mg/kg) and naringin (40 and 80 mg/kg) drug treatment were administered orally for six weeks to male wistar rats. Various behavioral performance tasks, biochemical, mitochondrial oxidative parameters, and aluminum concentration in the brain were assessed. Aluminum chloride treatment significantly caused cognitive dysfunction and mitochondria oxidative damage as compared to vehicle treated control group. Besides, aluminum chloride treatment significantly increased acetyl cholinesterase activity and aluminum concentration in the brain as compared to sham. Chronic administration of naringin significantly improved cognitive performance and attenuated mitochondria oxidative damage, acetyl cholinesterase activity, and aluminum concentration in aluminum-treated rats as compared to control rats. Results of the study demonstrate neuroprotective potential of naringin against aluminum chloride-induced cognitive dysfunction and mitochondrial oxidative damage.

Gastrointestinal Changes and Alzheimer's Disease.

BACKGROUND: There is a well-described mechanism of communication between the brain and gastrointestinal system in which both organs influence the function of the other. This bi-directional communication suggests that disease in either organ may affect function in the other. OBJECTIVE: To assess whether the evidence supports gastrointestinal system inflammatory or degenerative pathophysiology as a characteristic of Alzheimer's disease (AD). METHODS: A review of both rodent and human studies implicating gastrointestinal changes in AD was performed. RESULTS: Numerous studies indicate that AD changes are not unique to the brain but also occur at various levels of the gastrointestinal tract involving both immune and neuronal changes. In addition, it appears that numerous conditions and diseases affecting regions of the tract may communicate to the brain to influence disease. CONCLUSION: Gastrointestinal changes represent an overlooked aspect of AD, representing a more system influence of this disease.

Protective effect of curcumin (Curcuma longa) against D-galactose-induced senescence in mice.

Brain senescence plays an important role in cognitive dysfunction and neurodegenerative disorders. Curcumin was reported to have beneficial effect against several neurodegenerative disorders including Alzheimer's disease. Therefore, the present study was conducted in order to explore the possible role of curcumin against D-galactose-induced cognitive dysfunction, oxidative damage, and mitochondrial dysfunction in mice. Chronic administration of D-galactose for 6 weeks significantly impaired cognitive function (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity), and mitochondrial enzyme complex activities (I, II, and III) as compared to vehicle treated group. Curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment for 6 weeks significantly improved cognitive tasks, locomotor activity, oxidative defense, and restored mitochondrial enzyme complex activity as compared to control (D-galactose). Chronic D-galactose treatment also significantly increased acetylcholine esterase activity that was attenuated by curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment. In conclusion, the present study highlights the therapeutic potential of curcumin against d-galactose induced senescence in mice.

Therapeutic development of group B Streptococcus meningitis by targeting a host cell signaling network involving EGFR.

Group B Streptococcus (GBS) remains the most common Gram-positive bacterium causing neonatal meningitis and GBS meningitis continues to be an important cause of mortality and morbidity. In this study, we showed that GBS penetration into the brain occurred initially in the meningeal and cortex capillaries, and exploits a defined host cell signaling network comprised of S1P2 , EGFR, and CysLT1. GBS exploitation of such network in penetration of the blood-brain barrier was demonstrated by targeting S1P2 , EGFR, and CysLT1 using pharmacological inhibition, gene knockout and knockdown cells, and gene knockout animals, as well as interrogation of the network (up- and downstream of each other). More importantly, counteracting such targets as a therapeutic adjunct to antibiotic therapy was beneficial in improving the outcome of animals with GBS meningitis. These findings indicate that investigating GBS penetration of the blood-brain barrier provides a novel approach for therapeutic development of GBS meningitis.

Effect of St. John's Wort (Hypericum perforatum) treatment on restraint stress-induced behavioral and biochemical alteration in mice.

BACKGROUND: A stressful stimulus is a crucial determinant of health and disease. Antidepressants are used to manage stress and their related effects. The present study was designed to investigate the effect of St. John's Wort (Hypericum perforatum) in restraint stress-induced behavioral and biochemical alterations in mice. METHODS: Animals were immobilized for a period of 6 hr. St. John's Wort (50 and 100 mg/kg) was administered 30 minutes before the animals were subjecting to acute immobilized stress. Various behavioral tests parameters for anxiety, locomotor activity and nociceptive threshold were assessed followed by biochemical assessments (malondialdehyde level, glutathione, catalase, nitrite and protein) subsequently. RESULTS: 6-hr acute restraint stress caused severe anxiety like behavior, antinociception and impaired locomotor activity as compared to unstressed animals. Biochemical analyses revealed an increase in malondialdehyde, nitrites concentration, depletion of reduced glutathione and catalase activity as compared to unstressed animal brain. Five days St. John's Wort treatment in a dose of 50 mg/kg and 100 mg/kg significantly attenuated restraint stress-induced behavioral (improved locomotor activity, reduced tail flick latency and antianxiety like effect) and oxidative damage as compared to control (restraint stress). CONCLUSION: Present study highlights the modest activity of St. John's Wort against acute restraint stress induced modification.

Involvement of the nitric oxide signaling in modulation of naringin against intranasal manganese and intracerbroventricular ß-amyloid induced neurotoxicity in rats.

Manganese -induced aggregation of the amyloid-ß peptide (Aß) is a hallmark molecular feature of Alzheimer's disease (AD). The current study was designed to investigate the effects of chronic administration of naringin against ß-A1-42 and manganese induced experimental model. Wistar rats received intracerebroventricular (ICV) ß-A1-42 once, intranasal manganese, naringin and nitric oxide modulators for 21 days and behavioral alterations were assessed. Mitochondrial enzymes, oxidative parameters, TNF-α, ß-A1-42 acetylcholinesterase (AChE) levels and manganese concentration were measured. ICV ß-A1-42 and intranasal manganese treated rats showed a memory deficit and significantly increased in ß-A1-42 level and manganese concentration, mitochondrial oxidative damage, AChE level and inflammatory mediator in the hippocampus and cortex. Chronic administration of naringin (40 and 80 mg/kg) significantly improved memory performance and attenuated the oxidative damage and mitochondrial dysfunction in Aß with Mn treated rats. In addition, naringin also attenuates the pro-inflammatory cytokines like TNF-α, AChE, Amyloid deposition and Mn concentration. Further, pretreatment of N(G)-Nitro-L-arginine methyl ester (L-NAME) with (5 mg/kg) with lower dose of naringin significantly potentiated its protective effect. These results demonstrate that naringin offers protection against ICV ß-A1-42 and intranasal manganese induced memory dysfunction possibly due to its antioxidant, anti-inflammatory, anti-amyloidogenesis therefore, could have a therapeutic potential in Alzheimer's disease.

Development and application of a high-content virion display human GPCR array.

Human G protein-coupled receptors (GPCRs) respond to various ligands and stimuli. However, GPCRs rely on membrane for proper folding, making their biochemical properties difficult to study. By displaying GPCRs in viral envelopes, we fabricated a Virion Display (VirD) array containing 315 non-olfactory human GPCRs for functional characterization. Using this array, we found that 10 of 20 anti-GPCR mAbs were ultra-specific. We further demonstrated that those failed in the mAb assays could recognize their canonical ligands, suggesting proper folding. Next, using two peptide ligands on the VirD-GPCR array, we identified expected interactions and novel interactions. Finally, we screened the array with group B Streptococcus, a major cause of neonatal meningitis, and demonstrated that inhibition of a newly identified target, CysLTR1, reduced bacterial penetration both in vitro and in vivo. We believe that the VirD-GPCR array holds great potential for high-throughput screening for small molecule drugs, affinity reagents, and ligand deorphanization.

Protective effects of Aporosa octandra bark extract against D-galactose induced cognitive impairment and oxidative stress in mice.

Aporosa octandra (Buch.-Ham. ex D.Don) Vickery is a native species of India. Different parts of the plant are used for the medicinal purpose by the tribal peoples of south-eastern part of India. However, the biological properties of A. octandra have not been studied well. The extracts obtained from the bark of A. octandra were evaluated to determine their protective effect on cognitive impairment and oxidative stress in mice induced by D-galactose using the standard protocol. Different dosages of extract AOE-4 (100, 200, and 300 mg/kg, p.o.) were administered to mice, which were previously treated for six weeks with D-galactose (100 mg/kg s.c.). The D-galactose-induced mice showed significantly impaired cognitive behavior, i.e., oxidative defense, compared to the sham group. Six weeks of treatment with A. octandra extract AOE-4 (100, 200 and 300 mg/kg, p.o.) considerably improved the cognitive behavior and oxidative impairment of mice compared to the control alone (D-galactose). For the phytochemical investigation, the bark of A. octandra was successively extracted with dichloromethane and methanol. The chemical constituents of A. octandra were isolated by multiple column chromatography and characterized by different spectral analyses. (R)-Coclaurine (AO-5), an alkaloid, was isolated along with two other compounds from the AOE-4 extract; three more compounds were also isolated from the AOE-1 extract of the bark of A. octandra. All the compounds were isolated for the first time from the bark of A. octandra, and their structures were established by detailed spectral studies. The structure of compound AO-5 was also investigated and confirmed by X-ray diffraction and DFT studies. This study highlights the protective effect of A. octandra bark extract against D-galactose-induced biochemically dysfunction in mice. (R)-Coclaurine (AO-5) was isolated as one of the major components of A. octandra bark from AOE-4 extract; this compound could be further evaluated for the development of new potential drug candidates.

Possible role of endothelin receptor against hyperhomocysteinemia and ß-amyloid induced AD type of vascular dementia in rats.

Vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). The study was designed to investigate the effect of endothelin receptor against ß-amyloid induced AD type of vascular dementia. This disease was induced by combine administration of single ICV (intracerebroventricle) infusion of ß-amyloid (Aß) once and chronic oral administration of l-Methionine for 21 days. Bosentan (dual endothelin receptor antagonist) was administered for 21 days. Behavioral alterations were observed during different time interval of the study. Animals were killed immediately following the last behavior session. Oxidative parameters, acetylcholinesterase activity, neuro-inflammatory markers, amyloid beta levels were determined in hippocampus and cortex while serum homocysteine, serum nitrite carotid artery superoxide anion level were also determined. Endothelial function was measured on isolated carotid artery using myograph instrument. Aß+l-Methionine showed more significant development of cognitive and vascular endothelial deficits, manifested in terms of increase in serum homocysteine level, endothelial dysfunction, impairment of learning and memory, enhanced brain acetylcholinesterase activity, marked mito-oxidative damage in rats. We have observed that l-Methionine and combination of Aß+l-Methionine significantly enhanced Aß level both in cortex as well as hippocampus. Treatment of bosentan attenuated Aß+l-Methionine induced impairment of learning and memory, enhanced Aß level, mitochondrial and endothelial dysfunction. The results of present study concluded that bosentan offers protection against ß-amyloid-induced vascular dementia in rats. Endothelin receptor may be considered as a potential pharmacological target for the management of AD type of vascular dementia.

Antioxidant-Rich Fraction of Urtica dioica Mediated Rescue of Striatal Mito-Oxidative Damage in MPTP-Induced Behavioral, Cellular, and Neurochemical Alterations in Rats.

Parkinson's disease (PD) having a complex and multi-factorial neuropathology includes mainly the degeneration of the dopaminergic nigrostriatal pathway, which is a cumulative effect of depleted endogenous antioxidant enzymes, increased oxidative DNA damage, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. The present study was designed to investigate the neuroprotective effect of a potent antioxidant from Urtica dioica in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. MPTP was administered intranigrally for the induction of PD in male Wistar rats. Behavioral alterations were assessed in between the study period. Animals were sacrificed immediately after behavioral session, and different biochemical, cellular, and neurochemical parameters were measured. Intranigrally repeated administration of MPTP showed significant impairment of motor co-ordination and marked increase of mito-oxidative damage and neuroinflammation in rats. Intranigral MPTP significantly decreases the dopamine and its metabolites with impairment of dopaminergic cell density in rat brain. However, post-treatment with the potent antioxidant fraction of Urtica dioica Linn. (UD) (20, 40, 80 mg/kg) improved the motor function, mito-oxidative defense alteration significantly and dose dependently in MPTP-treated rats. In addition, the potent antioxidant fraction of UD attenuated the pro-inflammatory cytokines (TNF-α and IL-ß) and restored the level of dopamine and its metabolites in MPTP-induced PD in rats. Moreover, minocycline (30 mg/kg) with lower dose of UD (20 mg/kg) had significantly potentiated the protective effect of minocycline as compared to its effect with other individual drug-treated groups. In conclusion, Urtica dioica protected the dopaminergic neurons probably by reducing mito-oxidative damage, neuroinflammation, and cellular alteration along with enhanced neurotrophic potential. The above results revealed that the antioxidant rich fraction of UD contain flavonoids and phenolic compounds, which have a promising approach in therapeutics of PD.

Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats.

Previously explored combination therapies mostly involved the use of bioactive molecules. It is believed that herbal compounds containing multiple plant products have synergistic hepatoprotective effects and could enhance the desired actions. To investigate the combination of ethanolic fruits extract of Solanum xanthocarpum (SX) and Juniperus communis (JC) against Paracetamol (PCM) and Azithromycin (AZM) induced liver toxicity in rats. Liver toxicity was induced by combine oral administration of PCM (250 mg/kg) and AZM (200 mg/kg) for 7 days in Wistar rats. Fruit extract of SX (200 and 400 mg/kg) and JC (200 and 400 mg/kg) were administered daily for 14 days. The hepatoprotective activity was assessed using liver functional test, oxidative parameters and histopathological examination. The results demonstrated that combine administration of AZM and PCM significantly produced liver toxicity by increasing the serum level of hepatic enzymes and oxidative parameters in liver of rats. Histopathological examination also indicated that AZM and PCM produced liver damage in rats. Chronic treatment of SX and JC extract significantly and dose-dependently attenuated the liver toxicity by normalizing the biochemical factors and no gross histopathological changes were observed in liver of rats. Furthermore, combine administration of lower dose of SX and JC significantly potentiated their hepatoprotective effect which was significant as compared to their effect per se. The results clearly indicated that SX and JC extract has hepatoprotective potential against AZM and PCM induced liver toxicity due to their synergistic anti-oxidant properties.