Pharmacological Mechanism of Herbal Interventions for Bipolar Disorder.

Bipolar disorder is a neuropsychiatric disease characterized by an abundance of undesired ideas and thoughts associated with recurrent episodes of mania or hypomania and depression. Alterations in the circuits, including the prefrontal cortex, striatum, and limbic system, regulate mood and cause variation in several crucial neurotransmitters, including serotonin, dopamine, GABA, and glutamate. Imbalances in dopamine levels have been implicated in the manic phase, while variance in serotonin is linked to depressive episodes. The precise pathophysiology of bipolar disorder is still unknown. Though different treatments are available, like lithium, risperidone, valproic acid, etc., which are widely used, they come with certain limitations, including narrow therapeutic index, hypothyroidism, weight gain, extrapyramidal symptoms, etc. The interest in herbal- based treatments for bipolar disorder arises from the desire for alternative, potentially more natural, and holistic approaches with fewer side effects. The current review focuses on the potential effects of herbal drugs and their derivatives to alleviate the symptoms of bipolar disorder.

Influence of toll-like receptor-4 antagonist on bacterial load of asthma in Swiss albino mice: targeting TLR4/MD2 complex pathway.

Air pollution and environmental issues significantly impact life, resulting in the emergence and exacerbation of allergic asthma and other chronic respiratory infections. The main objective of this study is to suppress allergic asthma by TAK-242 from lipopolysaccharide-induced airway inflammation primarily stimulating toll-like receptor-4, and also to determine the potential mechanism of asthma eradication. The TAK-242 anti-allergic action was assured through the ovalbumin murine model of asthma via bronchial hyperresponsiveness and inflammation of the respiration tract in a pre-existing allergic inflammation paradigm. Swiss albino mice were sensitized and then challenged by ovalbumin and lipopolysaccharide for 5 days straight. TAK-242 reaction was assessed by inflammatory cytokines, and inflammatory cell count was determined from blood serum and bronchoalveolar lavage fluid, as well as group-wise regular weight assessments. After ovalbumin, lipopolysaccharide infusion, toll-like receptor-4 agonists caused a substantial increase in airway hyperresponsiveness, specific cellular inflammation, histological alterations, and immune mediator synthesis, as well as dose-related body-weight variations. A decrease in lipopolysaccharide-induced leukocyte count and Th1/Th17 related cytokines, TNF-α, and IL-6 expression through the ELISA study was particularly noticeable. Finally in treated groups, TAK-242, a TLR4/MD2 complex inhibitor, reduced airway inflammation and histopathological changes, cytokine expression, and body-weight management. TAK-242 has been found in an ovalbumin allergic asthma model to be a potential inhibitor of lipopolysaccharide-induced respiratory infection.

Effect of TLR3/dsRNA complex inhibitor on Poly(I:C)-induced airway inflammation in Swiss albino mice.

Rhinovirus infection frequently causes COPD and asthma exacerbations. Impaired anti-viral signaling and reduced viral clearance have both been seen in sick bronchial epithelium, potentially increasing exacerbations. Polyinosinic:polycytidylic acid (Poly(I:C)), a Toll-like receptor-3 (TLR3) ligand, has been shown to cause a viral exacerbation of severe asthma by detecting double-stranded RNA (dsRNA). The purpose of this work was to determine the effect of a TLR3/dsRNA complex inhibitor-Calbiochem drug in the prevention of Poly(I:C)-induced airway inflammation following TLR3 activation and to uncover a potential pathway for the cure of asthma through TLR3 inhibition. Mice were sensitized with Poly(I:C) as an asthma model before being challenged by PBS and ovalbumin (OVA) chemicals. The mice were administered a TLR3/dsRNA complex inhibitor. Throughout the trial, the mice's body weight was measured after each dosage. Biochemical methods are used to analyze the protein as well as enzyme composition in airway tissues. BALF specimens are stained using Giemsa to identify inflammatory cells and lung histopathology to determine morphological abnormalities in lung tissues. By using the ELISA approach, cytokine levels such as TNF-α, IL-13, IL-6, IL-5, and IgE antibody expression in lung tissue and blood serum were assessed. TLR3/dsRNA complex inhibitor drug significantly lowered the number of cells in BALF and also on Giemsa staining slides. It also downregulated the level of TNF-α and IL-6 in contrast to OVA and Poly(I:C) administered in animals. A TLR3/dsRNA complex inhibitor decreased the fraction of oxidative stress markers (MDA, GSH, GPx, and CAT) in lung tissues while keeping the mice's body weight constant during the treatment period. By decreasing alveoli, bronchial narrowing, smooth muscle hypertrophy, and granulocyte levels, the TLR3/dsRNA complex blocker significantly reduced the histopathological damage caused by OVA and Poly(I:C) compounds. In an animal model utilizing ovalbumin, TLR3/dsRNA complex inhibitors similarly reduced the bronchial damage produced by Poly(I:C). A novel TLR3/dsRNA complex inhibitor is expected to be employed in clinical studies since it suppresses airway inflammation without inducing antiviral approach resistance.

Metabolomics of neurological disorders in India.

Metabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.

First report of stem smut caused by Tranzscheliella hypodytes (Schltdl.) Vanky & McKenzie on Leymus secalinus (Georgi) Tzvelev in India.

Leymus secalinus (Blue wild rye) is a perennial grass species distributed in Leh-Ladakh region of India. Culms are usually solitary, 20-100 cm tall, 2-5-noded, smooth and glabrous. It is found on mountain slopes, rocky, stony and pebbled soils, grassy places, river banks, sandy and alkaline soils. It is one of the dominant species of the region and is mostly used for forage and grazing. L. secalinus plants with blackish-brown powdery spore mass/sori on the culm was observed in Leh region of Jammu and Kashmir, India during a wheat germplasm exploration (to collect wild relatives, land races, cultivars etc. of cultivated wheat) in September, 2018. Initially, sori were covered by the leaf sheath and at later stage more or less exposed with the absence of peridium. Infected culms and leaves are stunted, while inflorescences are abortive. Spores are globose, sub-globose to ovoid, blackish-brown in color, 3-5 x 4-4.5 µm in size, wall 0.5 µm thick and smooth. The fungus was identified as Tranzscheliella hypodytes (Schltdl.) Vanky & McKenzie based on morphological characteristics (Li et al. 2017; Vanky 2012, 2003; Vanky and McKenzie 2002). The ustilospore germination was not observed on potato dextrose agar during the lab experiment. In some cases, ustilospore germination is recorded in other smut fungi which shows considerable variation according to media and conditions used (Ingold, 1983). Moreover, there is no report available for the artificial culture of T. hypodytes. Identity was confirmed using the internal transcribed spacer (ITS) region of ribosomal DNA, amplified with universal primers ITS1 which was then sequenced. NCBI-BLAST showed 99.28% similarity with the ITS sequences of Tranzscheliella hypodytes (GenBank accession no. MH855460.1). The sequence was deposited in NCBI GenBank with accession number (MN108147). Pathogenecity test was conducted in glasshouse wherein smut infected samples of L. secalinus collected from Leh were made into small pieces and mixed with the sterilized soil filled in three pots before sowing. In addition, seeds were also mixed with smut spores before sowing. Inoculated pots after sowing were kept at 16±20C temperature and a relative humidity of 70% in a glass house. Control pots were maintained without inoculum. Inoculated and control pots were placed in separate chambers of the same glasshouse. Seventy days after sowing, inoculated plants were symptomatic, matching those described above and produced no seed. Pathogen reisolated from infected plants was identical in all respects to the isolate used to inoculate the plants, which confirmed the Koch's postulates. Control plants remained healthy and produced seed. Leh region is covered by sparse vegetation due to its topography and cold desert climate (cold, dry winter and warm, dry summer with very low precipitation, occuring in temperate region). Stem smut in L. secalinus can have significant negative impact on the fodder and grazing situation of the region. To our knowledge, this is the first report of stem smut caused by T. hypodytes on L. secalinus in India. A voucher specimen of the fungus was deposited at Herbarium Cryptogamae Indiae Orientialis (HCIO) (52182), ICAR-Indian Agricultural Research Institute, New Delhi.

1 H NMR metabolomic profiling elucidated attenuation of neurometabolic alterations by lercanidipine in MCAo model in rats.

OBJECTIVES: Stroke is a leading cause of death and disability worldwide with limited therapeutic interventions. The current study explored proton nuclear magnetic resonance spectroscopy (1 H NMR)-based metabolomic approach to elucidate the effect of lercanidipine on neurometabolic alterations in transient model of ischaemic stroke in rats. METHODS: In the present investigation, male Wistar rats were subjected to middle cerebral artery occlusion (MCAo) for 2 h followed by reperfusion using intraluminal filament method. Rats were randomly divided into three groups as vehicle-treated sham control, vehicle-treated MCAo control and lercanidipine-treated MCAo. Vehicle or lercanidipine (0.5 mg/kg, i.p.) was administered 120 min post-reperfusion. The rat brain cortex tissues were isolated 24 h post-MCAo and were investigated by 1 H NMR spectroscopy through perchloric extraction method. KEY FINDINGS: A total of 23 metabolites were altered significantly after cerebral ischaemic-reperfusion injury in MCAo control as compared to sham control rats. Lercanidipine significantly reduced the levels of valine, alanine, lactate, acetate and tyrosine, while N-acetylaspartate, glutamate, glutamine, aspartate, creatine/phosphocreatine, choline, glycerophosphorylcholine, taurine, myo-inositol and adenosine di-phosphate were elevated as compared to MCAo control. CONCLUSIONS: Present study illustrates effect of lercanidipine on neurometabolic alterations which might be mediated through its antioxidant, anti-inflammatory, vasodilatory and anti-apoptotic property in MCAo model of stroke.

Citalopram attenuated neurobehavioral, biochemical, and metabolic alterations in transient middle cerebral artery occlusion model of stroke in male Wistar rats.

Oxidative stress and inflammation are implicated as cardinal mechanisms of neuronal death following stroke. In the present study citalopram (Cit) was investigated in a 2 h middle cerebral artery occlusion (MCAo) model of stroke in male Wistar rats. Pretreatment, posttreatment (Post Cit) and pre plus posttreatment (Pre + Post Cit) with Cit were evaluated for its neuroprotective effect. In pretreatment protocol, effect of Cit at three doses (2, 4, and 8 mg/kg) administered i.p., 1 h prior to MCAo was evaluated using neurological deficit score (NDS), motor deficit paradigms, and cerebral infarction 24 h post-MCAo. In posttreatment and pre plus posttreatment protocol, the effective dose of Cit (4 mg/kg) was administered i.p., 0.5 h post-reperfusion (Post Cit) only, and 1 h prior to MCAo and again at 0.5 h post-reperfusion (Pre + Post Cit), respectively. These two groups were assessed for NDS and cerebral infarction. Though NDS was significantly reduced in both Post Cit and Pre + Post Cit groups, significant reduction in cerebral infarction was evident only in Pre + Post Cit group. Infarct volume assessed by magnetic resonance imaging was significantly attenuated in Pre + Post Cit group (10.6 ± 1.1%) compared to MCAo control group (18.5 ± 3.0%). Further, Pre + Post Cit treatment significantly altered 17 metabolites along with attenuation of malondialdehyde, reduced glutathione, matrix metalloproteinases, and apoptotic markers as compared to MCAo control. These results support the neuroprotective effect of Cit, mediated through amelioration of oxidative stress, inflammation, apoptosis, and altered metabolic profile.

Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats.

Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1mg/kg, i.p.) was administered 60min prior MCAo. The rats were assessed 24h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120min post-reperfusion to assess vasodilatory property of lercanidipine (0.5mg/kg, i.p.) administered at two different time points: 60min post-MCAo and 15min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5mg/kg, i.p.) was administered 15min, 120min and 240min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24h post-MCAo, effectiveness was evident upto 120min. For sub-acute studies same dose/vehicle was repeated for next 3days and magnetic resonance imaging (MRI) was performed 96h after the last dose. Biochemical markers estimated in rat brain cortex 24h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120min post-reperfusion, but failed to show vasodilatation with 15min post-reperfusion group. Lercanidipine (13.78±2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90±2.44%) investigated 96h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as compared to control group. Biochemical alterations were significantly ameliorated by lercanidipine till 120min post-reperfusion group and MMP-9 inhibition observed even with 240min group. Thus, lercanidipine revealed significant neuroprotective effect mediated through attenuation of oxidative stress, inflammation and apoptosis.

Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Zizyphus jujuba is used for anticonvulsant, hypnotic-sedative, anxiolytic, tranquilizer, antioxidant and anti-inflammatory properties. Likewise silymarin is popularly used for its potent antioxidant and hepatoprotective effects. Stroke being a multifactorial disease with unsatisfactory treatment outcomes, necessitates development of multimodal therapeutic interventions. Thus, we evaluated the therapeutic benefits of herbal combination of Z. jujuba and silymarin in a focal cerebral ischemia model. AIM OF THE STUDY: To evaluate the neuroprotective potential of hydroalcoholic extract of Z. jujuba (HEZJ) fruit and silymarin alone and in combination in middle cerebral artery occlusion (MCAo) model of focal cerebral ischemia in rats. MATERIALS AND METHODS: Male Wistar rats were pretreated with HEZJ (100, 250 and 500mg/kg, p.o.) or silymarin (250mg/kg, p.o.) for 3 days prior to induction of MCAo. Neurological deficit score, motor impairment and cerebral infarction were assessed 24h following MCAo. HEZJ (250mg/kg) co-administered with silymarin (250mg/kg) for 3 days prior to induction of MCAo was also evaluated for above parameters and oxidative stress. Malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) levels in the cortex, striatum and hippocampal brain regions were estimated 24h post MCAo. RESULTS: Pretreatment with HEZJ and silymarin reduced the neurological deficit score, motor impairment and cerebral infarction volume. HEZJ and silymarin pretreatment also ameliorated the oxidative stress in different brain regions, which was evident from increased SOD levels, decreased MDA and NO levels as compared to MCAo control rats. Interestingly neuroprotective efficacy was potentiated by pretreatment with HEZJ and silymarin combination. CONCLUSION: Pretreatment with HEZJ and silymarin combination was observed to have better neuroprotection mediated via amelioration of oxidative stress in the focal cerebral ischemia model.

Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists.

Cannabinoid 1 (CB1) receptors have the ability to change conformation between active (R*) and inactive (R) receptor states. Herein, we further characterize these receptor states using series of saturation radioligand binding studies and their differential displacement binding by various CB1 receptor ligands. Binding experiments were carried out in naïve rat/dog whole brain membranes using radioligands [(3)H]CP55,940 (for R* state) & [(3)H]SR141716A (both R* and R states) and various agonist, antagonist & inverse agonist ligands at CB1 receptors. In the saturation binding experiments, of the total number of CB1 receptor binding sites (R* + R) in the rat and dog whole brain membranes, only about 18.3 and 11.6% were in the active (R*) state recognized by [(3)H]CP55,940, respectively. In the competitive binding studies, all the CB1 receptor agonists investigated had significantly very high affinity for the active R* state recognized by [(3)H]CP55,940 and lower affinity for the inactive R state mainly recognized by [(3)H]SR141716A in the presence of a non-hydrolyzable analogue of GTP [Gpp(NH)p]. In contrast, various CB1 receptor antagonists/inverse agonists had similar nanomolar affinities at both [(3)H]CP55,940 and [(3)H]SR141716A recognized binding states. These results clearly characterize the significant differences between the active R* and inactive R binding states of CB1 receptors in naive rat and dog brain. In addition, these results also demonstrates that the CB1 agonists and antagonists/inverse agonists can be differentiated by their relative affinities at active (R*) and inactive (R) binding states of the CB1 receptor.

Neuroprotective effect of MnTMPyP, a superoxide dismutase/catalase mimetic in global cerebral ischemia is mediated through reduction of oxidative stress and DNA fragmentation.

Excessive generation of free radicals and decreased levels of the antioxidant enzymes such as superoxide dismutase (SOD) and catalase have been observed after brain ischemic reperfusion injury. In the present study, we have investigated the neuroprotective potential of MnTMPyP (Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride), a SOD/Catalase mimetic in bilateral carotid artery occlusion model of global cerebral ischemia in Mongolian gerbils. Five minutes of bilateral carotid artery occlusion produced global cerebral ischemia, which was evident from the neurological deficits, spontaneous motor activity and the decrease in the number of viable hippocampal CA1 neurons. Global ischemia was also associated with increased levels of malondialdehyde, decreased levels of SOD and catalase, and increased TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) positive cells, indicating oxidative stress and DNA fragmentation. Administration of a single dose of MnTMPyP, 1 mg/kg i.p. (30 min before occlusion), produced no significant neuroprotection; however, 3 mg/kg i.p. (30 min before to occlusion) produced significant reduction in neurological score, spontaneous motor activity and CA1 pyramidal neuronal damage. MnTMPyP also attenuated the increased levels of malondialdehyde and improved the levels of SOD and catalase, and inhibited DNA fragmentation in the ischemic animals. Multiple administration of MnTMPyP, 3 mg/kg i.p. (three times: 30 min before, 1 h and 3 h after occlusion), produced better neuroprotection as compared to single dose administration. This study demonstrates that the neuroprotective effect of MnTMPyP in global ischemia is mediated through reduction in oxidative stress and DNA fragmentation.

Neuroprotective effects of trolox in global cerebral ischemia in gerbils.

Stroke is a third leading cause of death and oxygen free radicals have been shown to be involved in its pathophysiology. In the present study, we have investigated neuroprotective potential of trolox, a free radical scavenger in bilateral carotid arteries occlusion (5 min) model of global cerebral ischemia in Mongolian gerbils. Gerbils were treated with trolox (3, 10 or 30 mg/kg, i.p.) 30 min prior to occlusion. There was a significant increase in neurological symptoms and locomotor activity in ischemic animals as compared with the sham-operated animals. These effects were attenuated by trolox 30 mg/kg, i.p. Significant increase in the number of the surviving neurons in the hippocampal CA1 pyramidal region was observed in ischemic animals treated with trolox 30 mg/kg, i.p. There was significant increase in the level of malondialdehyde (MDA) in ischemic animals indicating oxidative stress. Elevated levels of MDA in ischemic animals (25.79+/-3.34 microM/mg of protein) were reduced (16.43+/-3.32 microM/mg of protein) and (8.98+/-0.89 microM/mg of protein) by trolox 10 and 30 mg/kg, i.p., respectively. This study demonstrates the neuroprotective potential of trolox in global cerebral ischemia in gerbils.