Amelioration of Aluminum Maltolate-Induced Inflammation and Endoplasmic Reticulum Stress-Mediated Apoptosis by Tannoid Principles of Emblica officinalis in Neuronal Cellular Model.

The neuroprotective role of tannoid principles of Emblica officinalis (EoT), an Indian and Chinese traditional medicinal plant against memory loss in aluminum chloride-induced in vivo model of Alzheimer's disease through attenuating AChE activity, oxidative stress, amyloid and tau toxicity, and apoptosis, was recently reported in our lab. However, to further elucidate the mechanism of neuroprotective effect of EoT, the current study was designed to evaluate endoplasmic reticulum stress-suppressing and anti-inflammatory role of EoT in PC 12 and SH-SY 5Y cells. These cells were divided into four groups: control (aluminum maltolate (Al(mal)3), EoT + Al(mal)3, and EoT alone based on 3-(4, 5-dimethyl 2-yl)-2, and 5-diphenyltetrazolium bromide (MTT) assay. EoT significantly reduced Al(mal)3-induced cell death and attenuated ROS, mitochondrial membrane dysfunction, and apoptosis (protein expressions of Bax; Bcl-2; cleaved caspases 3, 6, 9, 12; and cytochrome c) by regulating endoplasmic reticulum stress (PKR-like ER kinase (PERK), α subunit of eukaryotic initiation factor 2 (EIF2-α), C/EBP-homologous protein (CHOP), and high-mobility group box 1 protein (HMGB1)). Moreover, inflammatory response (NF-κB, IL-1ß, IL-6, and TNF-α) and Aß toxicity (Aß1-42) triggered by Al(mal)3 was significantly normalized by EoT. Our results suggested that EoT could be a possible/promising and novel therapeutic lead against Al-induced neurotoxicity. However, further extensive research is needed to prove its efficacy in clinical studies.

Phosphodiesterase-4 inhibitors ameliorates cognitive deficits in deoxycorticosterone acetate induced hypertensive rats via cAMP/CREB signaling system.

Phosphodiesterase-4 (PDE-4) inhibitors promote memory by blocking the degradation of cAMP. Existing evidence also shows that neuronal survival and plasticity are dependent on the phosphorylation of cAMP-response element-binding protein. In this regard, PDE-4 inhibitors have also been shown to reverse pharmacologically and genetically induced memory impairment in animal models. In the present study, the authors examined the effect of both rolipram and roflumilast (PDE-4 inhibitors) on the impairment of learning and memory observed in hypertensive rats. Deoxycorticosterone acetate (DOCA) salt hypertensive model was used to induce learning and memory deficits. The mRNA expression of different PDE-4 subtypes along with the protein levels of pCREB and BDNF in the hippocampus was quantified. Systolic blood pressure was significantly increased in DOCA salt hypertensive rats when compared to sham operated rats. This effect was reversed by clonidine, an α2 receptor agonist, while PDE-4 inhibitors did not. PDE-4 inhibitors significantly improved the time-induced memory deficits in object recognition task (ORT). In DOCA salt hypertensive rats, the gene expression of PDE-4B and PDE-4D was significantly increased. Furthermore, both pCREB and BDNF showed decreased levels of expression in hypertensive rats in comparison to sham operated rats. Repeated administration of PDE-4 inhibitors significantly decreased both PDE-4B and PDE-4D with an increase in the expression of pCREB and BDNF in hypersensitive rats. Also, rolipram, roflumilast and roflumilast N-oxide showed a linear increase in the plasma and brain concentrations after ORT. Our present findings suggested that PDE-4 inhibitors ameliorate hypertension-induced learning impairment via cAMP/CREB signaling that regulates BDNF expression downstream in the rat hippocampus.

Memantine exerts functional recovery by improving BDNF and GDNF expression in 3-nitropropionic acid intoxicated mice.

Memantine (MN), a NMDA blocker is well known for its protective effect against various neurodegenerative diseases. However, its role in improving motor function and regulation of neurotrophic factors in Huntington's disease (HD) has not been studied yet. In the present study, we have investigated the effect of MN against 3-nitropropionic acid (3NP), induced motor impairment, and alterations in the expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in mice brain. Further, its role in mitochondrial function was assessed by measuring succinate dehydrogenase (SDH) activity. Glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) immunoreactivity were studied to evaluate the role of MN on glial and neuronal function. Its effect on apoptosis was adjudged by studying the expression of apoptotic markers. MN restored motor functions with an associated up-regulation in neurotrophin expression. MN also enhanced brain SDH activity and decreased glutamate content. MN ameliorated striatal neuronal loss, reduced GFAP immunoreactivity, and exhibited protective effect against neuronal apoptosis. Data from the current study demonstrated that MN exerted neuroprotective effect against 3NP induced neuropathology. Restoration of motor function by MN might be through regulation of neurotrophin expression. MN can therefore be a useful therapeutic choice in the symptomatic management of HD.

Alteration in bioenergetic regulators, SirT1 and Parp1 expression precedes oxidative stress in rats subjected to transient cerebral focal ischemia: molecular and histopathologic evidences.

The present study was undertaken to identify the time-dependent changes in bioenergetic regulators and oxidative stress markers levels and also to ascertain which occurs early in focal cerebral ischemia. The status of bioenergetic regulators (nicotinamide adenine dinucleotide, Silent information regulator Transporter 1 (SirT1) and Poly adenosine diphosphate--ribose polymerase 1 (Parp1)) and oxidative stress markers' (lipid peroxidation and nitric oxide) levels along with excitatory neurochemical glutamate, neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), and caspase 3 at various durations of reperfusion viz 0, 1, 6, 24, 72, and 166 hours was investigated in rats subjected to 2 hours of middle cerebral artery occlusion. Six hours after reperfusion, a significant downregulation in SirT1 and upregulation in Parp1 expressions were observed in striatal region of ischemic-reperfused rats compared with ischemic rats. Peak elevation in glutamate content was recorded at 72 hours, and maximum level of lipid peroxidation and nitric oxide contents were observed at 166 hours. A significant decrease in NeuN and increase in GFAP-positive cells were observed at 24 and 72 hours, respectively, in cortical, striatal, and hippocampal regions. These data reveal that change in bioenergetic regulators occurs earlier than excitotoxicity and oxidative stress in cerebral stroke. From the data, it can also be inferred that appropriate therapeutic intervention, that is, bioenergetic modulators at early period and either glutamatergic and/or antioxidant therapy at delayed period may yield a better therapeutic outcome.

Prenatal exposure to lamotrigine: effects on postnatal development and behaviour in rat offspring.

Use of antiepileptic drugs (AEDs) in pregnancy warrants various side effects and also deleterious effects on fetal development. The present study was carried out to assess the effects of prenatal exposure to lamotrigine (LTG) on postnatal development and behavioural alterations of offspring. Adult male and female Sprague Dawley rats weighing 150-180 g b. wt. were allowed to copulate and pregnancy was confirmed by vaginal cytology. Pregnant rats were treated with LTG (11.5, 23, and 46 mg/kg, p.o) from gestational day 3 (GND 3) and this treatment continued till postnatal day 11 (PND 11). Offspring were separated from their dam on day 21 following parturition. LTG, at 46 mg/kg, p.o, produced severe clinical signs of toxicity leading to death of dam between GND 15 and 17. LTG, at 11.5 and 23 mg/kg, p.o, showed significant alterations in offspring's incisors eruption and vaginal opening when compared to age matched controls. LTG (23 mg/kg, p.o) exposed female offspring expressed hyperactive behaviour and decreased GABA-A receptor expression when compared to control rats. These results reveal that prenatal exposure to LTG may impart differential postnatal behavioural alterations between male and female rats which paves way for further investigations.

Polyphenols in madhumega chooranam, a Siddha medicine, ameliorates carbohydrate metabolism and oxidative stress in type II diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Present study was undertaken to demonstrate the mode of anti-diabetic action of a polyherbal Siddha Medicine, Madhumega chooranam (MMC). MATERIALS AND METHODS: MMC was fractionated into phenolic (PMMC) and non-phenolic (NPMMC) portions in order to identify bioactive fraction. Study was performed in type II diabetic rats. Role of PMMC and NPMMC on liver glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucokinase and glycogen content were determined. Their role on superoxide dismutase, reduced glutathione and lipid peroxidation were investigated. In addition, their effects on GLUT4 and PPARγ gene expression were studied. Pancreas and liver histopathology was studied using hematoxylin and eosin stain. RESULTS: PMMC improved carbohydrate metabolism by decreasing glucose-6-phosphatase and fructose-1,6-bisphosphatase and increasing glucokinase and glycogen contents in diabetic rats liver. It alleviated oxidative stress by increasing superoxide dismutase, glutathione and decreasing lipid peroxidation content. PMMC up-regulated liver GLUT4 and PPARγ mRNA expression in comparison to the vehicle or NPMMC rats. CONCLUSION: Madhumega chooranam mediates its anti-diabetic action through the inhibition of gluconeogenesis and activation of glycolytic pathways in type II diabetic rats. Increased GLUT4 and PPARγ expressions provide additional information on its glucose uptake/sensitising and hypolipidemic potential. Phenolic components of MMC were found to be the bioactive principles.