Neurotrophic Factor Mediated Neurorestorative Effect of Pongamia pinnata Against Transient Cerebral Hypoperfusion and Reperfusion in Rats: Preliminary Histological and Molecular Level Evidence

SUMMARY: Stroke is the leading cause of acquired physical disability in adults and second leading cause of mortality throughout the world. Treatment strategies to curb the effects of stroke would be of great benefit. Pongamia pinnata is a recent attraction in medicine, owing to its abundant medicinal benefits with minimal side effects. The present study aimed to examine acute and subacute effect of Pongamia pinnata leaf extract on transient cerebral hypoperfusion and reperfusion (tCHR) in Wistar rats. 24 adult Wistar rats (12 each for acute and subacute study) were divided in to four groups each viz normal control group, tCHR + NS group, tCHR + 200mg/kg bw and tCHR + 400mg/kg bw groups. Cerebral ischemia induction was carried out by bilateral common carotid artery occlusion and reperfusion. Ethanolic extract of Pongamia pinnata leaves were orally administered for 7 days and 21 days after the surgical procedure for acute and subacute study respectively. Behavioural analysis, histological assessment, and estimation of mRNA levels of HIF-1, GDNF, BDNF and NF-kB were performed. In both acute and subacute study, there was significant improvement in the beam walking assay, neuronal count, decreased neuronal damage in histological sections and higher mRNA expression of BDNF and GDNF in the treatment groups. There was no significant difference in the expression of HIF1 and NF-kB. Thus, Pongamia pinnata has excellent neurorestorative property reversing many of the effects of ischemic stroke induced by tCHR in rats with the underlying mechanism being an improvement in the expression of neurotrophic factors GDNF and BDNF.

El ataque cerebrovascular es la principal causa de discapacidad física adquirida en adultos y la segunda causa de mortalidad en todo el mundo. Las estrategias de tratamiento para frenar los efectos del ataque cerebrovascular serían de gran beneficio. Pongamia pinnata es una atracción reciente en la medicina, debido a sus abundantes beneficios medicinales con mínimos efectos secundarios. El presente estudio tuvo como objetivo examinar el efecto agudo y subagudo del extracto de hoja de Pongamia pinnata sobre la hipoperfusión y reperfusión cerebral transitoria (tCHR) en ratas Wistar. Se dividieron 24 ratas Wistar adultas (12 cada una para el estudio agudo y subagudo) en cuatro grupos, el grupo control normal, el grupo tCHR + NS, los grupos tCHR + 200 mg/kg de peso corporal y tCHR + 400 mg/kg de peso corporal. La inducción de la isquemia cerebral se llevó a cabo mediante oclusión y reperfusión bilateral de la arteria carótida común. El extracto etanólico de hojas de Pongamia pinnata se administró por vía oral durante 7 días y 21 días después del procedimiento quirúrgico para estudio agudo y subagudo respectivamente. Se realizaron análisis de comportamiento, evaluación histológica y estimación de los niveles de ARNm de HIF-1, GDNF, BDNF y NF-kB. Tanto en el estudio agudo como en el subagudo, hubo una mejora significativa en el ensayo de desplazamiento del haz, el recuento neuronal, una disminución del daño neuronal en las secciones histológicas y una mayor expresión de ARNm de BDNF y GDNF en los grupos con tratamiento. No hubo diferencias significativas en la expresión de HIF1 y NF-kB. Por lo tanto, Pongamia pinnata tiene una excelente propiedad neurorestauradora que revierte muchos de los efectos del ataque cerebrovascular isquémico inducido por tCHR en ratas, siendo el mecanismo subyacente una mejora en la expresión de los factores neurotróficos GDNF y BDNF.

Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates ß-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus.

BACKGROUND: Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. METHODS AND RESULTS: Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10 days. Subsequently, a single dose of 40 mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200 mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10 mg/kg) or luteolin (50 mg/kg or 100 mg/kg) once daily for 28 days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic ß-cells and kidneys to near normalcy. CONCLUSION: Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, ß-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.

Luteolin Mitigates Diabetic Dyslipidemia in Rats by Modulating ACAT-2, PPARα, SREBP-2 Proteins, and Oxidative Stress.

Diabetic dyslipidemia is a crucial link between type-2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular diseases (ASCVD). Natural biologically active substances have been advocated as complementary remedies for ASCVD and T2DM. Luteolin, a flavonoid, exhibits antioxidant, hypolipidemic, and antiatherogenic effects. Hence, we aimed to determine influence of luteolin on lipid homeostasis and hepatic damage in rats with T2DM induced by high-fat-diet (HFD) and streptozotocin (STZ). After being fed HFD for 10 days, male Wistar rats received 40 mg/kg STZ intraperitoneal injection on 11th day. Seventy-two hours later, hyperglycemic rats (fasting glucose > 200 mg/dL) were randomized into groups, and oral hydroxy-propyl-cellulose, atorvastatin (5 mg/kg), or luteolin (50 mg/kg or 100 mg/kg) administered daily, while continuing HFD for 28 days. Luteolin significantly ameliorated dyslipidemia levels and concomitantly improved atherogenic index of plasma in a dose-dependent manner. Increased levels of malondialdehyde and diminished levels of superoxide dismutase, catalase, and glutathione in HFD-STZ-diabetic rats were significantly regulated by luteolin. Luteolin significantly intensified PPARα expression while decreasing expression of acyl-coenzyme A:cholesterol acyltransferase-2 (ACAT-2) and sterol regulatory element binding protein-2 (SREBP-2) proteins. Moreover, luteolin effectively alleviated hepatic impairment in HFD-STZ-diabetic rats to near-normal control levels. The findings of the present study expound mechanisms by which luteolin mitigated diabetic dyslipidemia and alleviated hepatic impairment in HFD-STZ-diabetic rats by amelioration of oxidative stress, modulation of PPARα expression, and downregulation of ACAT-2 and SREBP-2. In conclusion, our results imply that luteolin may be efficacious in management of dyslipidemia in T2DM, and future research may be essential to substantiate our findings.

Rhizophora mucronata Lam. (Mangrove) Bark Extract Reduces Ethanol-Induced Liver Cell Death and Oxidative Stress in Swiss Albino Mice: In Vivo and In Silico Studies.

The bark extract of Rhizophora mucronata (BERM) was recently reported for its prominent in vitro protective effects against liver cell line toxicity caused by various toxicants, including ethanol. Here, we aimed to verify the in vivo hepatoprotective effects of BERM against ethanol intoxication with the prediction of potential targets employing in silico studies. An oral administration of different concentrations (100, 200 and 400 mg/kg body weight) of BERM before high-dose ethanol via intraperitoneal injection was performed in mice. On day 7, liver sections were dissected for histopathological examination. The ethanol intoxication caused liver injury and large areas of necrosis. The pre-BERM administration decreased the ethanol-induced liver damage marker tumor necrosis factor-alpha (TNF-α) expression, reduced hepatotoxicity revealed by nuclear deoxyribonucleic acid (DNA) fragmentation and decreased oxidative stress indicated by malondialdehyde and glutathione contents. Our in silico studies have identified BERM-derived metabolites exhibiting the highest predicted antioxidant and free radical scavenger activities. Molecular docking studies showed that most of the metabolites were predicted to be enzyme inhibitors such as carbonic anhydrase inhibitors, which were reported to stimulate the antioxidant defense system. The metabolites predominantly presented acceptable pharmacokinetics and safety profiles, suggesting them as promising new antioxidant agents. Altogether, the BERM extract exerts antioxidative activities and shows promising hepatoprotective effects against ethanol intoxication. Identification of related bioactive compounds will be of interest for future use at physiological concentrations in ethanol-intoxicated individuals.

Embelin and levodopa combination therapy for improved Parkinson's disease treatment.

Parkinson's disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.

Efficacy of different intensity of aquatic exercise in enhancing remyelination and neuronal plasticity using cuprizone model in male Wistar rats.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Most exercise studies concentrate on the impact of exercise on cardiovascular system; this study aims to present the effects of exercise of varying intensity on the nervous system. Most recently in MS, positive outcomes were obtained with resistance and high-intensity exercises. This study also analyzes the effects of a prior conditioning program before the induction of demyelination and subsequent neuroprotective effects of such program. OBJECTIVES: To study and determine the neuroprotective and remyelinating effects of different intensity of aquatic exercise and a preconditioning exercise program on demyelination induced by oral administration of cuprizone (Cup). MATERIAL AND METHODS: Six groups of animals, each containing 6 rats, were used in the study. The groups were as follows: group I - control group; group II - Cup group; group III - treated with methylprednisolone (MP); group IV - treated with low-intensity exercise (LIE), free swimming for 40 min and high-intensity exercise (HIE); group V - treated with a resistance of 9% body weight and free swimming for 40 min; group VI - treated with preconditioning exercise (free swimming for 40 min for 3 weeks) before Cup administration followed by the same exercise protocol as for group V. All data were analyzed using one-way analysis of variance (ANOVA) with Tukey's test, by means of SigmaPlot v. 14.5 software. RESULTS: Similarly to the MP group, group VI showed a positive outcome. A value of p < 0.001 was considered statistically significant. Also, group VI showed improved areas of remyelination in histopathology, an increased expression of myelin basic protein (MBP), reduced expression of glial fibrillary acidic protein (GFAP) in corpus callosum, and improved gene expression of brain-derived neurotrophic factor (BDNF) in the hippocampus region. CONCLUSIONS: General fitness achieved through a preconditioning program combined with HIE showed neuroprotective effects, as evidenced by increased areas of remyelination and improved neuronal plasticity, observed mostly in group VI (conditioning+HIE).

Purine metabolites can indicate diabetes progression.

AIM: To find the association between purine metabolites and diabetic complications in rats. MATERIALS AND METHODS: Alloxan was administered to induce diabetes in rats. After 30 days, the levels of uric acid, inosine, xanthine, hypoxanthine and AMP were assessed in both plasma and liver tissues using HPLC technique. RESULTS: A significant increase in xanthine, hypoxanthine, AMP levels (p < .001 and t-value 2.78) and inosine in plasma and liver tissues (p < .05 and t-value 2.11) with a concomitant increase in uric acid levels (p < .001 and t-value 2.80) was observed in diabetic group. CONCLUSION: Purine metabolites like uric acid and other intermediate products of purine metabolism are increased in diabetes. These results can be used in addition or separately in evaluating the progression of diabetes.

Vestibular stimulation: a noninvasive brain stimulation in Parkinson's disease & its implications.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and it is characterized by both motor and neuropsychiatric problems. Effective treatment of PD requires a combination of pharmacotherapy and physiotherapy; however, existing treatment generally involves one medical discipline most probably interpretation by neurologist. This pharmacotherapy relay on dopaminergic medications which is not capable of bringing sufficient alleviation of all motor symptoms in PD. Implementing positive lifestyle activities can support patients to improve the quality of life, symptoms, and possibly slow down the disease progression. In far effective management of PD, clinics are trying to execute and promote the use of additional integrative approaches of care among PD patients. Notably, vestibular stimulation like noisy galvanic vestibular stimulation (nGVS) is being studied as a potential treatment for PD, and a number of studies have presented scientific evidence in support of this concept. In this review paper, we highlight the importance of vestibular stimulation in both human and animal studies as one of the promising interventional approaches for PD. All the existing studies are heterogeneous in study design, so further studies have to be conducted which meets the standards of randomized control trial with proper sample size to validate the findings of vestibular stimulation.

Evaluation of the sub-acute toxicity of Acacia catechu Willd seed extract in a Wistar albino rat model.

Acacia catechu (A. catechu) or Khair (Hindi) is used in several herbal preparations in the Ayurvedic system of medicine in India. Traditionally, this drug is beneficial against several gastrointestinal and stomach related ailments, and leprosy. The present investigation was carried out to evaluate the sub-acute oral toxicity of the ethanolic extract of A. catechu seeds in Wistar albino rats. Results obtained from the quantitative chemical analysis of A. catechu seed extract were compared with commercially available standards. A. catechu seed extract was administered orally at the doses of 250, 500 and 1000 mg/kg b.w. daily for 28 days. General behavior, bodyweight and mortality were examined during the entire study period. At the end of 28 days, hematological and biochemical parameters along with the relative organ weights were determined. It was observed that the extract did not induce death or any significant changes in the body weight, relative weight of vital organs and in hematological parameters for up to a dose of 1000 mg/kg. The oral administration of the plant extract did not produce any significant changes in the levels of glucose. In addition, there were no significant changes in the activity of both hepatotoxic and nephrotoxic marker enzymes in the serum. Oral administration of A. catechu also did not produce any significant changes in the levels of oxidative markers. Furthermore, the findings from the biochemical studies were, well corroborated with the histological findings.

Amyloid protein aggregates: new clients for mitochondrial energy production in the brain?

Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitochondria support transcriptional regulation and proteostatic signaling mechanisms through crosstalk between the mitochondria itself, the nucleus, and the cytoplasm. Mitochondrial dysfunction leads to impaired proteostasis, and both are key pathological features of age-related neurological disorders. For example, Alzheimer's and Parkinson's diseases feature mitochondrial-targeted protein aggregates and impaired mitochondrial function, although the mechanistic causes are poorly understood. Vascular abnormalities and hypometabolism in such neurological diseases are reported several years before key clinical disease symptoms even become apparent. Recent investigations suggest that processing of such aggregates within mitochondria can offer protective functions, specifically by restoring energy (ATP) in starving cells. We hypothesize that the accumulation of protein aggregates in mitochondria can not only disrupt its functions, but also render a protective role to fulfill energy demands in hypometabolic conditions. Growing evidence favors mitochondrial defense to toxic amyloid aggregates/oligomers as a protective response. In this viewpoint article, we will present several publications (in addition to our own) that serve to connect the possible role of protein aggregates in mitochondrial energy production for degenerative conditions.

Conformational Preferences of Aß25-35 and Aß35-25 in Membrane Mimicking Environments.

BACKGROUND: The structural transition of aggregating Abeta peptides is the key event in the progression of Alzheimer's Disease (AD). OBJECTIVE: In the present work, the structural modifications of toxic Aß25-35 and the scrambled Aß35-25 were studied in Trifluoroethanol (TFE) and in aqueous SDS micelles. METHODS: Using CD spectroscopic investigations, the conformational transition of Aß25-35 and Aß35-25 peptides were determined in different membrane mimicking environments such as TFE and SDS. An interval scan CD of the peptides on evaporation of TFE was performed. TFE titrations were carried out to investigate the intrinsic ability of the structural conformations of peptides. RESULTS: We show by spectroscopic evidence that Aß25-35 prefers beta sheet structures upon increasing TFE concentrations. On the other hand, the non-toxic scrambled Aß35-25 peptide only undergoes a transition from random coil to α-helix conformation with increasing TFE. In the interval scan studies, Aß25-35 did not show any structural transitions, whereas Aß35-25 showed transition from α-helix to ß-sheet conformation. In membrane simulating aqueous SDS micelles, Aß25-35 showed a transition from random coil to α-helix while Aß35-25 underwent transition from random coil to ß-sheet conformation. CONCLUSION: Overall, the current results seek new insights into the structural properties of amyloidogenic and the truncated sequence in membrane mimicking solvents.

Characterization of Brain Dysfunction Induced by Bacterial Lipopeptides That Alter Neuronal Activity and Network in Rodent Brains.

The immunopathological states of the brain induced by bacterial lipoproteins have been well characterized by using biochemical and histological assays. However, these studies have limitations in determining functional states of damaged brains involving aberrant synaptic activity and network, which makes it difficult to diagnose brain disorders during bacterial infection. To address this, we investigated the effect of Pam3CSK4 (PAM), a synthetic bacterial lipopeptide, on synaptic dysfunction of female mice brains and cultured neurons in parallel. Our functional brain imaging using PET with [18F]fluorodeoxyglucose and [18F] flumazenil revealed that the brain dysfunction induced by PAM is closely aligned to disruption of neurotransmitter-related neuronal activity and functional correlation in the region of the limbic system rather than to decrease of metabolic activity of neurons in the injection area. This finding was verified by in vivo tissue experiments that analyzed synaptic and dendritic alterations in the regions where PET imaging showed abnormal neuronal activity and network. Recording of synaptic activity also revealed that PAM reorganized synaptic distribution and decreased synaptic plasticity in hippocampus. Further study using in vitro neuron cultures demonstrated that PAM decreased the number of presynapses and the frequency of miniature EPSCs, which suggests PAM disrupts neuronal function by damaging presynapses exclusively. We also showed that PAM caused aggregation of synapses around dendrites, which may have caused no significant change in expression level of synaptic proteins, whereas synaptic number and function were impaired by PAM. Our findings could provide a useful guide for diagnosis and treatment of brain disorders specific to bacterial infection.SIGNIFICANCE STATEMENT It is challenging to diagnose brain disorders caused by bacterial infection because neural damage induced by bacterial products involves nonspecific neurological symptoms, which is rarely detected by laboratory tests with low spatiotemporal resolution. To better understand brain pathology, it is essential to detect functional abnormalities of brain over time. To this end, we investigated characteristic patterns of altered neuronal integrity and functional correlation between various regions in mice brains injected with bacterial lipopeptides using PET with a goal to apply new findings to diagnosis of brain disorder specific to bacterial infection. In addition, we analyzed altered synaptic density and function using both in vivo and in vitro experimental models to understand how bacterial lipopeptides impair brain function and network.

Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer's Disease.

Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer's disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (ß-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of ß-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aß is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other ß-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

Pluchea lanceolata protects hippocampal neurons from endothelin-1 induced ischemic injury to ameliorate cognitive deficits.

Ischemic brain injury is one of the leading causes of death and disability, where lack of disease modifying treatment strategies make us rely on symptomatic relief. Treatment principles from traditional systems of medicine may fill this gap and its validation in modern medicine perspective is important to bring them to mainstream. Here, we evaluated the neuroprotective efficacy of Ayurvedic medicinal herb Pluchea lanceolata in treating ischemic hippocampal injury. Focal hippocampal ischemia was modeled in Wistar rats through stereotaxic intrahippocampal injection of endothelin-1 (ET-1). Post-surgery, hydroalcoholic extract of the rhizome of Pluchea lanceolata (HAPL) was administered orally, once in a day for 14 consecutive days to ischemic rats. There were two treatment groups based on the HAPL dosage; HAPL200 (200 mg/kg body weight) and HAPL400 (400 mg/kg body weight). Comparisons were made with the ET-1 ischemic rats which received only the vehicle, and the normal surgical control. Ischemic hippocampal injury led to severe cognitive deficits as evaluated by Morris water maze and open field test, along with locomotory dysfunction noted in actophotometer test. HAPL treatment significantly attenuated these behavioural deficits in a dose dependent manner. Loss of pyramidal cells and degenerative phenotype of shrunken hyperdensed soma with pyknotic nuclei in CA1 and CA3 hippocampal neurons in ischemia were reversed after HAPL treatment. We provide first evidence for loss of dendritic architecture in ET-1 induced focal ischemic hippocampal injury using Golgi impregnation, where HAPL could salvage the dendritic branching and intersections. Intriguingly, it enhanced the dentritic arborization beyond what is noted in normal rats. Ability of HAPL to reverse oxidative stress, especially through maintaining glutathione peroxidase levels and lipid peroxidation in ischemic condition evidences that it may exert neuroprotection through its antioxidant properties. Thus, Pluchea lanceolata and its constituents provide potential alternative/adjuvant treatment strategy for ischemic hippocampal stroke.

Safety Evaluation of Various Vector Repellents in Combination with Deltamethrin in Wistar Rats.

BACKGROUND: Vector repellents are used globally to avoid insect bites and control transmission of diseases. It is important to ensure safety levels of these compounds, although they are noxious to insects. Vector repellents when used in combination are known to bring additional benefits in getting rid of the harmful insects. Unfortunately, the safety levels of various vector repellents such as Deet (N,N-diethyl-m-toluamide), Depa (N,N-diethyl phenylacetamide), and Deb (N,N-diethylbenzamide) are not studied in combination with the widely used pyrethroid deltamethrin (Del). MATERIALS AND METHODS: In this study, safety evaluation of various vector repellents by oral route in combination with Del was studied by assessing body weight and organ weight changes, hematological parameters, and biochemical parameters in Wistar rats. RESULTS: The results revealed significant changes in liver marker enzymes in Del, Deb, Del + Depa, and Del + Deet groups. Urea levels were significantly altered after treatment with various repellents and in combination with Del, except Deb-alone group. Hematological and rest of the biochemical parameters were found to be unaltered in all the treatment groups. Significant changes in the liver weight were found in Deb, Depa, Deet, Del + Deb, and Del + Deet groups. CONCLUSIONS: Taken together, the overall results of this study indicate that single, high oral dose of various insect repellents did not show any additive toxicity.

Protective Effect of Pluchea lanceolata against Aluminum Chloride-induced Neurotoxicity in Swiss Albino Mice.

BACKGROUND: Aluminum chloride (AlCl3) is a known potent environmental neurotoxin causing progressive neurodegenerative changes in the brain. The herb Pluchea lanceolata is commonly known as "Rasana" and used as a nerve tonic in neuroinflammatory conditions in Indian system of medicine. OBJECTIVE: To evaluate the neuroprotective activity of hydroalcoholic extract of P. lanceolata in chronic AlCl3-induced neurotoxicity in Swiss albino mice. MATERIALS AND METHODS: Albino mice were categorized into four different groups; Group 1served as vehicle control, Group 2 mice were administered with AlCl3, 40 mg/kg body weight by intraperitoneal route for 45 consecutive days. Groups 3 and 4 mice were administered with AlCl3, 40 mg/kg body weight intraperitoneal for 45 consecutive days along with hydroalcoholic extract of P. lanceolata at 200 and 400 mg/kg body weight. RESULTS: Chronic administration of AlCl3 resulted in behavioral deficits, triggered lipid peroxidation, increased acetylcholinesterase (AChE) activity, and histological alterations. Co-administration of hydroalcoholic extract of P. lanceolata attenuated many of the AlCl3-induced alterations such as behavioral, lipid peroxidation, AChE, and histological changes of brain tissue. CONCLUSION: The results of the present study have demonstrated the protective role of hydroalcoholic extract of P. lanceolata against AlCl3-induced neurotoxicity in Swiss albino mice. The neuroprotective efficacy of P. lanceolata can help reduce the symptoms caused by toxic protein aggregates in several degenerative diseases. SUMMARY: The hydro alcoholic extract of Pluchea lanceolata showed neuroprotective activity in albino mice against AlCl3 toxicityThe benefits of Pluchea lanceolata against AlCl3 toxicity includes reduced lipid peroxidation and acetylcholine esterase activity with improved behavioral functionsThe hydro alcoholic extract of Pluchea lanceolata rendered protection against AlCl3 in forebrain, midbrain, cerebellum and hippocampusTherefore Pluchea lanceolata holds pharmacological potentials for treating diseases associated with neuronal toxicity. Abbreviations used: HAPL: Hydro alcoholic extract of Pluchea lanceolata; CAT: Catalase; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; TBARS: Thio-barbituric acid reactive substances; MDA: Malondialdehyde; AChE: Acetylcholine esterase; AOT: Acute oral toxicity; CNS: Central nervous system; H2O2: Hydrogen peroxide; ML: molecular layer; GL: granular layer; MC: microcytic changes; BV: blood vessels; DG: dentate gyrus; PC: pyramidal cells; LD: Lethal dose; ANOVA: Analysis of variance; SEM: Standard error of mean; PCL: Pyramidal cell layer; OCL: Outer granular layer; BV: blood vessels; PM: Pia mater.

TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C +/+) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific. We show that female Tia1-knockout (Tia1 -/-) mice gain significant body weight (BW) during early postnatal development. We next examined the effect of Tia1 deletion in novel C +/+/Tia1 -/- mice. Underscoring the opposing effects of Tia1 deletion and low SMN level on BW gain, both C +/+ and C +/+/Tia1 -/- females showed similar BW gain trajectory at all time points during our study. We observed early tail necrosis in C +/+/Tia1 -/- females but not in males. We show enhanced impairment of male reproductive organ development and exacerbation of the C +/+/Tia1 -/- testis transcriptome. Our findings implicate a protein factor as a gender-specific modifier of a mild mouse model of SMA.

Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking?

OBJECTIVE: We provide a contemporary account of the key pathologic events pertaining to autism: the theory of oxidative stress and inflammatory causes, ideas of immune dysfunction, the probable biomarkers that can be used for diagnostics, and the use of pharmaceuticals and stem cells as possible candidates for the treatment of autism spectrum disorders (ASDs). METHODS: ASDs are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention and impaired social and communication skills. ASDs are also associated with numerous functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. RESULTS: Although the exact causes of ASDs are unknown, it is suggested that genetic, epigenetic, and environmental factors play critical roles. More recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. CONCLUSIONS: Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive.

Hypoxia-inducible factors as neuroprotective agent in Alzheimer's disease.

Beta amyloid (Aß)-42 peptide and phosphorylated tau protein have been demonstrated as the pathological hallmarks of Alzheimer's disease (AD). A gradual decline of oxygen and glucose supply to the brain during aging or hypoxia was manifested as a contributing factor to hypometabolism. The brain regions susceptible to hypometabolism are the hippocampus, entorhinal cortex and cognition-associated neocortical regions like parietal, temporal and frontal cortex. In AD patients, the brain regions with hypometabolism can trigger overexpression of amyloid precursor protein and decrease the clearance of Aß. Aß and hypoxia can evoke inflammation, oxidative stress and finally neuronal cell death. Among the transcription factors involved in the compensatory mechanism, hypoxia-inducible factor-1 alpha (HIF-1α) has a major role in the cellular adaptation by inducing the expression of several proteins, including vascular endothelial growth factor, erythropoietin and inducible nitric oxide synthase. Therefore, maintaining the HIF-1α level by inhibiting the prolyl 4-hydroxylase was effective to attenuate the nerve damage during hypoxia and postpone the incidence of AD. Agents such as iron chelators, and heavy metals like cobalt and nickel were demonstrated to be effective in maintaining the HIF-1α level in the nerve. This review article discusses the possible role of HIF-1α as a neuroprotector in AD and the future perspectives.