Neuroprotective effects of vitamin B1 on memory impairment and suppression of pro-inflammatory cytokines in traumatic brain injury.

Traumatic Brain Injury (TBI) remains one of the prevailing disorders that affect millions of people around the globe. There is a cascade of secondary attributes attached to TBI including excitotoxicity, axonal degeneration, neuroinflammation, oxidative stress, and apoptosis. Neuroinflammation is caused due to the activation of microglia along with pro-inflammatory cytokines. The activation of microglia triggers TNF-α which sequentially results in the triggering and upregulation of NF-kB. The aim of the current research was to investigate vitamin B1's potential as neuroprotective agent against TBI-induced neuroinflammation arbitrated memory impairment together with pre- and post-synaptic dysfunction in an adult albino male mice model. TBI was induced using the weight-drop method which caused the microglial activation resulting in neuroinflammation along with synaptic dysfunction leading to the memory impairment of the adult mice. Vitamin B1 was administered for seven days via the intraperitoneal pathway. To analyze the memory impairment and efficacy of vitamin B1, Morris water maze and Y-maze tests were performed. The escape latency time and short-term memories of the experimental mice treated with vitamin B1 were significantly different from the reference mice. The western blot results showed that vitamin B1 has reduced neuroinflammation by downregulating proinflammatory cytokines (NFκ-B, TNF- α). Vitamin B1 also proved its worthiness as a convincing neuroprotective agent by reducing memory dysfunction and recovering the activities of pre- and post-synapse via upregulation of synaptophysin and Postsynaptic density protein 95 (PSD-95).

Friedelin Attenuates Neuronal Dysfunction and Memory Impairment by Inhibition of the Activated JNK/NF-κB Signalling Pathway in Scopolamine-Induced Mice Model of Neurodegeneration.

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of ß-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-ß production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer's disease.

Anthocyanins encapsulated by PLGA@PEG nanoparticles potentially improved its free radical scavenging capabilities via p38/JNK pathway against Aß1-42-induced oxidative stress.

BACKGROUND: In order to increase the bioavailability of hydrophilic unstable drugs like anthocyanins, we employed a polymer-based nanoparticles approach due to its unique properties such as high stability, improved bioavailability and high water-soluble drug loading efficiency. Anthocyanins constitute a subfamily of flavonoids that possess anti-oxidative, anti-inflammatory and neuroprotective properties. However, anthocyanins are unstable because their phenolic hydroxyl groups are easily oxidized into quinones, causing a reduced biological activity. To overcome this drawback and improve the free radical scavenging capabilities of anthocyanins, in the current study we for the first time encapsulated the anthocyanins in biodegradable nanoparticle formulation based on poly (lactide-co-glycolide) (PLGA) and a stabilizer polyethylene glycol (PEG)-2000. The biological activity and neuroprotective effect of anthocyanin loaded nanoparticles (An-NPs) were investigated in SH-SY5Y cell lines. RESULTS: Morphological examination under transmission electron microscopy (TEM) showed the formation of smooth spherically shaped nanoparticles. The average particle size and zeta potential of An-NPs were in the range of 120-165 nm and -12 mV respectively, with a low polydispersity index (0.4) and displayed a biphasic release profile in vitro. Anthocyanins encapsulation in PLGA@PEG nanoparticles (NPs) did not destroy its inherent properties and exhibit more potent neuroprotective properties. An-NPs were nontoxic to SH-SY5Y cells and increased their cell viability against Aß1-42 by its free radical scavenging characteristics and abrogated ROS generation via the p38-MAPK/JNK pathways accompanied by induction of endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Comparative to native bulk anthocyanins, An-NPs effectively attenuated Alzheimer's markers like APP (amyloid precursor protein), BACE-1 (beta-site amyloid precursor protein cleaving enzyme 1), neuroinflammatory markers such as p-NF-kB (phospho-nuclear factor kappa B), TNF-α (tumor necrosis factor) and iNOS (inducible nitric oxide synthase) and neuroapoptotic markers including Bax, Bcl2, and Caspase-3 protein expressions accompanied by neurodegeneration against Aß1-42 in SH-SY5Y cell lines. CONCLUSIONS: Overall, this data not only confirmed the therapeutic potential of anthocyanins in reducing AD pathology but also offer an effective way to improve the efficiency of anthocyanins through the use of nanodrug delivery systems.

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain.

BACKGROUND: Glutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7. METHODS: PND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate. RESULTS: A single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity. CONCLUSIONS: Here, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.

Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain.

Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration.

Rho GTPase activating protein 15 (arhGAP15) siRNA effect apoptosis-induced by ethanol in bovine fibroblast cells.

The Rho GTPases are the sub-group of Ras super family and identified in all eukaryotes. The Rho GTPases effect different cellular signaling pathways involved in a number of diseases such as cancer, neurological and cardiovascular disorders. Members of Rho GTPases including RhoA, RhoC and Rac1 play a major role in regulation of apoptosis in different kind of stress conditions. Here we investigated the Rho GTPase activating protein 15 (ArhGAP15) gene knock-down effect on apoptosis induced by ethanol in bovine fibroblast cells. The bovine Fibroblast cells were treated and transfected with two different concentrations (50 and 100 nM) of ArhGAP15 siRNA for 48 h respectively. Both concentrations of siRNA were effective and the results of RT-PCR revealed an efficient knock-down of ArhGAP15 mRNA in fibroblast cells. Further, the normal cells exposed to a 100 mM ethanol concentration showed a reduction in cell viability and induced the ratio of apoptosis related Bax/Bcl-2 proteins compared with ArhGAP15 siRNA transfected ethanol treated cells. Ethanol also increased caspase-3 expression in normal fibroblast cells compared with transfected cells. The ArhGAP15 knock-down cells treated with ethanol decreased Bax/Bcl-2 ratio and lower caspase-3 protein levels in ArhGAP15 knocked-down cells. Our results suggest that apoptosis induced by ethanol involves the activation of Rho GTPase activating protein 15 and silencing of the said gene protects apoptosis.

Friedelin and Glutinol induce neuroprotection against ethanol induced neurotoxicity in pup's brain through reduction of TNF-α, NF-kB, caspase-3 and PARP-1.

Ethanol administration triggers an inflammatory response that leads to a complex series of immune responses including the release of an excessive amount of inflammatory mediators particularly tumor necrosis factor (TNF-α) and nuclear factor-kB (NF-KB) which produce a large amount of reactive oxygen species. The inflammatory-induced cytotoxicity is increased when the PI3-kinase/Akt pathway is inhibited. Some studies have also shown that ethanol suppresses the PI3-kinase signaling pathway induced by receptor activation. Friedelin and Glutinol belong to pentacyclic triterpenoid class and are known for their anti-inflammatory and antioxidant properties. The present study was aimed to elucidate the effects of these phytoconstituents on one of the key ethanol-induced neuronal damage pathways. The pups having (5-7 g average body weight) were used and randomly divided into groups. The control and ethanol treated pups were administered 0.9% normal saline while treated pups received glutinol and friedelin (30 mg/kg subcutaneously) respectively. After four hours all the experimental animals were sacrificed and their brains were collected carefully for protein expression analysis of p-Akt, TNF-α, NF-KB, caspase-3 and PARP-1 employing immunoblotting technique. Hemolytic, DNA protection, chelating power and ß-carotene assays results revealed that freidelin and glutinol are safe for parenteral administration. Glutinol administration with ethanol significantly abridged the ethanol induced over expression of TNF-α, caspase-3 and PARP-1 in pup's brain. Similarly, freidelin attenuated the neurodegeneration by inhibiting the ethanol induced p-JNK and NF-kB expression in pups' brain. This protection may be attributed to the revival of p-Akt signaling for cell survival. It is concluded that the present study demonstrates the neuro-protective effects of friedelin and glutinol via modulating the capase-3 and PARP-1 expression and modulating the neuronal apoptotic pathways.

Folicitin abrogates scopolamine induced oxidative stress, hyperlipidemia mediated neuronal synapse and memory dysfunction in mice.

No effective drug treatment is available for Alzheimer disease, thus the need arise to develop efficient drugs for its treatment. Natural products have pronounced capability in treating Alzheimer disease therefore current study aimed to evaluate the neuro-protective capability of folicitin against scopolamine-induced Alzheimer disease neuropathology in mice. Experimental mice were divided into four groups i.e. control (single dose of 250 µL saline), scopolamine-administered group (1 mg/kg administered for three weeks), scopolamine plus folicitin-administered group (scopolamine 1 mg/kg administration for three weeks followed by folicitin administration for last two weeks) and folicitin-administered group (20 mg/kg administered for 5 alternate days). Results of behavioral tests and Western blot indicated that folicitin has the capability of recovering the memory against scopolamine-induced memory impairment by reducing the oxidative stress through up-regulating the endogenous antioxidant system like nuclear factor erythroid 2-related factor and Heme oxygenase-1 while prohibiting phosphorylated c-Jun N-terminal kinase. Similarly, folicitin also improved the synaptic dysfunction by up-regulating SYP and PSD95. Scopolamine-induced hyperglycemia and hyperlipidemia were abolished by folicitin as evidenced through random blood glucose test, glucose tolerance test and lipid profile test. All these results revealed that folicitin being a potent anti-oxidant is capable of improving synaptic dysfunction and reducing oxidative stress through Nrf-2/HO-1 pathway, thus plays a key role in treating Alzheimer disease as well as possess hyperglycemic and hyperlipidemic effect. Furthermore, a detailed study is suggested.

Zinc Ortho Methyl Carbonodithioate Improved Pre and Post-Synapse Memory Impairment via SIRT1/p-JNK Pathway against Scopolamine in Adult Mice.

Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice. We post-administered ZOMEC (30 mg/Kg) into two group of mice for three weeks on daily basis that received either 0.9% saline or SCOP (1 mg/Kg) for initial two weeks. The other two groups of mice received 0.9% saline and SCOP (1 mg/Kg) respectively. After memory related behavioral analysis the brain homogenates were evaluated for the antioxidant potential of ZOMEC and multiple protein markers were examined through western blotting. Our results provide enough evidences that ZOMEC decrease oxidative stress by increasing catalase (CAT) and glutathione S transferase (GST) and decreasing the lipid peroxidation (LPO). The SIRT1 and pre and post synaptic marker proteins, synaptophysin (SYP) as well as post synaptic density protein (PSD-95) expression were also enhanced upon ZOMEC treatment. Furthermore, memory impairment was rescued and ZOMEC appreciably abrogated the Aß accumulation, BACE1 expression C and the p-JNK pathway. The inflammatory protein markers, NF-kß and IL-1ß in ZOMEC treated mice were also comparable with control group. The predicted interaction of ZOMEC with SIRT1 was further confirmed by molecular docking. These findings thus provide initial reports on efficacy of ZOMEC in SCOP induced AD model.

6-Aminoflavone Activates Nrf2 to Inhibit the Phospho-JNK/TNF-α Signaling Pathway to Reduce Amyloid Burden in an Aging Mouse Model.

In the current study, we examined the antioxidant activity and anti-amyloidogenic potential of 6-aminoflavone in an adult mice model of d-galactose-induced aging. Male albino eight-week-old mice were assigned into four groups: 1. the control group (saline-treated), 2. d-galactose-treated mice (100 mg/kg/day, intravenously) for eight weeks, 3. d-galactose-treated mice (100 mg/kg/day, intravenously for eight weeks) and 6-AF-treated mice (30 mg/kg/day, intravenously for the final four weeks), and 4. 6-AF-treated mice (30 mg/kg/day i.p. for four weeks). We conducted many assays for antioxidant enzymes, including lipid peroxidation, catalase, glutathione (GSH), peroxidase (POD), and sulfoxide dismutase (SOD) (LPO). Western blotting was used to assess protein expression while the Morris water maze (MWM) and Y-maze (YM) were used to study behavior. The findings show that 6-AF greatly improved neuronal synapse and memory impairment brought on by d-galactose and it significantly inhibited BACE1 to reduce the amyloidogenic pathway of A (both amyloid ß production and aggregation) by upregulating Nrf2 proteins (validated through molecular docking studies) and suppressing phosphorylated JNK and TNF-α proteins in adult albino mice's brain homogenates. These findings suggest that 6-AF, through the Nrf2/p-JNK/TNF-α signaling pathway, can diminish the oxidative stress caused by d-galactose, as well as the amyloidogenic route of A formation and memory impairment.

ZOMEC via the p-Akt/Nrf2 Pathway Restored PTZ-Induced Oxidative Stress-Mediated Memory Dysfunction in Mouse Model.

A new mechanistic approach to overcome the neurodegenerative disorders caused by oxidative stress in Alzheimer's disease (AD) is highly stressed in this article. Thus, a newly formulated drug (zinc ortho-methyl carbonodithioate (ZOMEC)) was investigated for five weeks on seven-week-old BALB/c male mice. ZOMEC 30 mg/kg was postadministered intraperitoneally during the third week of pentylenetetrazole (PTZ) injection. The brain homogenates of the mice were evaluated for their antioxidant potential for ZOMEC. The results including catalase (CAT), glutathione S transferase (GST), and lipid peroxidation (LPO) demonstrated that ZOMEC significantly reverted the oxidative stress stimulated by PTZ in the mouse brain. ZOMEC upregulated p-Akt/Nrf-2 pathways (also supported by molecular docking methods) to revoke PTZ-induced apoptotic protein markers. ZOMEC reversed PTZ-induced neuronal synapse deficits, improved oxidative stress-aided memory impairment, and inhibited the amyloidogenic pathway in mouse brains. The results suggested the potential of ZOMEC as a new, safe, and neurotherapeutic agent to cure neurodegenerative disorders by decreasing AD-like neuropathology in the animal PTZ model.

Complications of nose and paranasal sinus disease.

BACKGROUND: Diseases of nose and paranasal sinuses can complicate to involve the orbit and other surrounding structures because of their close proximity. These diseases are usually infective or can be neoplastic in origin. METHOD: All the patients presenting in ENT or Eye Departments of Ayub Teaching Hospital during the one year study period who had complicated nose or paranasal sinus disease were included in the study. A detailed history and examination followed by CT scanning and laboratory investigations to assess the type and extent of the disease, was carried out. RESULTS: Infections were the most common cause of complicated sinus disease 11 (75%). The rest of the 4 (25%) cases were tumours. 12 (80%) of the cases presented with proptosis. In I of these 12 cases. there was complete blindness. In 2 (13%) of the cases there was only orbital cellulitis. Two of these patients had facial swelling and 2 had nasal obstruction and presented as snoring. Two patients presented with history of weight loss and these patients had malignant tumour of the paranasal sinuses. One patient presented with early signs of meningitis. In 1 case subperiosteal scalp abscess (Pott's puffy tumour) was the only complication noted. CONCLUSION: Nose and paranasal sinus diseases can complicate to involve mostly the orbit, but sometimes brain, meninges and skull bones can also get involved.

Predicting Multi-Interfacial Binding Mechanisms of NLRP3 and ASC Pyrin Domains in Inflammasome Activation.

NLRP3-PYD inflammasome activates an inflammatory pathway in response to a wide variety of cell damage or infections. Dysregulated NLRP3 inflammatory signaling has many chronic inflammatory and autoimmune disorders. NLRP3 and ASC have a PYD, a superfamily member of the Death Domain, which plays a key role in inflammatory assembly. The ASC interacts with NLRP3 through a homotypic PYD and recruits the procaspase-1 through a homotypic caspase recruitment domain interaction. Here, we used several computational approaches to reveal the interactions of the NLRP3 and ASC PYD domains that lead to the activation of the inflammasome complex. We have characterized ASC and NLRP3-PYD intermolecular interactions by protein-protein docking, and further molecular dynamics (MD) simulations were conducted to evaluate the stability of NLRP3/ASC-PYD complex. Subsequently, we have identified several residues that stabilize the NLRP3/ASC-PYD complex in different faces (i.e., Face-1 to Face-4). The research framework offers new insights into the molecular mechanisms of inflammasome and apoptosis signaling as well as the ease of the drug discovery process.

Isolation, Characterization and Neuroprotective Activity of Folecitin: An In Vivo Study.

Neurodegenerative diseases (NDs) extend the global health burden. Consumption of alcohol as well as maternal exposure to ethanol can damage several neuronal functions and cause cognition and behavioral abnormalities. Ethanol induces oxidative stress that is linked to the development of NDs. Treatment options for NDs are yet scarce, and natural product-based treatments could facilitate ND management since plants possess plenty of bioactive metabolites, including flavonoids, which typically demonstrate antioxidant and anti-inflammatory properties. Hypericum oblongifolium is an important traditional medicinal plant used for hepatitis, gastric ulcer, external wounds, and other gastrointestinal disorders. However, it also possesses multiple bioactive compounds and antioxidant properties, but the evaluation of isolated pure compounds for neuroprotective efficacy has not been done yet. Therefore, in the current study, we aim to isolate and characterize the bioactive flavonoid folecitin and evaluate its neuroprotective activity against ethanol-induced oxidative-stress-mediated neurodegeneration in the hippocampus of postnatal day 7 (PND-7) rat pups. A single dose of ethanol (5 g/kg body weight) was intraperitoneally administered after the birth of rat pups on PND-7. This caused oxidative stress accompanied by the activation of phosphorylated-c-Jun N-terminal kinase (p-JNK), nod-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cysteine-aspartic acid protease-1 (caspase-1) proteins to form a complex called the NLRP3-inflammasome, which converts pro-interleukin 1 beta (IL-1B) to activate IL-1B and induce widespread neuroinflammation and neurodegeneration. In contrast, co-administration of folecitin (30 mg/kg body weight) reduced ethanol-induced oxidative stress, inhibited p-JNK, and deactivated the NLRP3-inflammasome complex. Furthermore, folecitin administration reduced neuroinflammatory and neurodegenerative protein markers, including decreased caspase-3, BCL-2-associated X protein (BAX), B cell CLL/lymphoma 2 (BCL-2), and poly (ADP-ribose) polymerase-1 (PARP-1) expression in the immature rat brain. These findings conclude that folecitin is a flavone compound, and it might be a novel, natural and safe agent to curb oxidative stress and its downstream harmful effects, including inflammasome activation, neuroinflammation, and neurodegeneration. Further evaluation in a dose-dependent manner would be worth it in order to find a suitable dose regimen for NDs.

Vitamin D exerts neuroprotection via SIRT1/nrf-2/ NF-kB signaling pathways against D-galactose-induced memory impairment in adult mice.

Vitamin D (Vt. D) is one of the vital hormone having multiple functions in various tissues, including brain. Several evidences reported that Vt. D plays a significant part in memory and cognition as its inadequate amount may accelerate cognitive impairment. This study shows for the first time the antioxidant potential of Vt. D against D-Galactose (D-gal) induced oxidative stress mediated Alzheimer disease (AD) pathology in male adult albino mice. The result reveals that the mice exposed to D-gal (120 mg/kg) for eight weeks have pre-and post-synaptic dysfunction and impaired memory investigated through Morris water maze and Y-maze tests. This is followed by the suppressed Nuclear factor erythroid 2-related factor 2 (NRF2), Heme Oxygenase-1 (HO-1) and elevated expressions of Nuclear Factor kappa B (NF-kB), Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1ß) proteins in the brain homogenates evaluated through western blotting technique. On the other hand Vt. D (100 µg/kg) administration (three times a week for 4 weeks) activated Silent mating type information regulation 2 homolog 1 (SIRT1) and significantly improved both the neuronal synapse and memory, reduced oxidative stress by upregulating NRF-2 and HO-1 and downregulating NF-kB, TNF-α and IL-1ß proteins expression. Most importantly, Vt. D significantly abrogate the amyloidogenic pathway of amyloid beta (Aß) production against D-gal in the brains of adult male albino mice. These results reveal that Vt. D being an antioxidant agent plays a vital role in reducing the AD pathophysiology in D-gal induced animal model of aging, therefore act as a potential drug candidate in neurodegenerative diseases.

Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-ß-Induced Mouse Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Aß) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated ß- and γ-secretase activities, leading to excessive Aß deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of Aß-mediated neurodegeneration and cognitive deficit. However, the effect of Aß on cholesterol metabolism is lesser-known. In this study, we evaluated the effect of quinovic acid (QA; 50 mg/kg body weight, i.p.) against the intracerebroventricular (i.c.v.) injection of Aß (1-42)-induced cholesterol dyshomeostasis, oxidative stress, and neurodegeneration in the cortex and hippocampal brain regions of wild-type male C57BL/6J mice. Our results indicated that Aß (1-42)-treated mice have increased Aß oligomer formation along with increased ß-secretase expression. The enhanced amyloidogenic pathway in Aß (1-42)-treated mice intensified brain cholesterol accumulation due to increased expressions of p53 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. Importantly, we further confirmed the p53-mediated HMGCR axis activation by using pifithrin-α (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to Aß (1-42)-injected mice significantly ameliorated the Aß burden, p53 expression, and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Moreover, the QA downregulated gliosis, neuroinflammatory mediators (p-NF-κB and IL-1ß), and the expression of mitochondrial apoptotic markers (Bax, cleaved caspase-3, and cytochrome c). QA treatment also reversed the deregulated synaptic markers (PSD-95 and synaptophysin) and improved spatial learning and memory behaviors in the Aß-treated mouse brains. These results suggest that Aß (1-42) induces its acute detrimental effects on cognitive functions probably by increasing brain cholesterol levels through a possible activation of the p53/HMGCR axis. However, QA treatment reduces the cholesterol-induced oxidative stress, neuroinflammation, and neurodegeneration, leading to the restoration of cognitive deficit after Aß (1-42) i.c.v. injection in mice.

Natural Antioxidant Anthocyanins-A Hidden Therapeutic Candidate in Metabolic Disorders with Major Focus in Neurodegeneration.

All over the world, metabolic syndrome constitutes severe health problems. Multiple factors have been reported in the pathogenesis of metabolic syndrome. Metabolic disorders result in reactive oxygen species (ROS) induced oxidative stress, playing a vital role in the development and pathogenesis of major health issues, including neurological disorders Alzheimer's disease (AD) Parkinson's disease (PD). Considerable increasing evidence indicates the substantial contribution of ROS-induced oxidative stress in neurodegenerative diseases. An imbalanced metabolism results in a defective antioxidant defense system, free radicals causing inflammation, cellular apoptosis, and tissue damage. Due to the annual increase in financial and social burdens, in addition to the adverse effects associated with available synthetic agents, treatment diversion from synthetic to natural approaches has occurred. Antioxidants are now being considered as convincing therapeutic agents against various neurodegenerative disorders. Therefore, medicinal herbs and fruits currently receive substantially more attention as commercial sources of antioxidants. In this review, we argue that ROS-targeted therapeutic interventions with naturally occurring antioxidant flavonoid, anthocyanin, and anthocyanin-loaded nanoparticles might be the ultimate treatment against devastating illnesses. Furthermore, we elucidate the hidden potential of the neuroprotective role of anthocyanins and anthocyanin-loaded nanoparticles in AD and PD neuropathies, which lack sufficient attention compared with other polyphenols, despite their strong antioxidant potential. Moreover, we address the need for future research studies of native anthocyanins and nano-based-anthocyanins, which will be helpful in developing anthocyanin treatments as therapeutic mitochondrial antioxidant drug-like regimens to delay or prevent the progression of neurodegenerative diseases, such as AD and PD.

17ß-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model.

Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17ß-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17ß-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress-mediated JNK/NF-Ò¡B overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17ß-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17ß-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17ß-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17ß-estradiol, in an ERα/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress-mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.

Evaluation of auditory perception skills development in profoundly deaf children following cochlear implantation.

BACKGROUND: Cochlear implant is a medical treatment option for individuals with severe to profound sensori-neural hearing loss on account of non-functioning cochlea or part thereof. Technology is ever evolving and the candidacy criteria are widening. Appropriate selection of patient, successful implantation of an appropriate device and adequate post-implantation rehabilitation protocol are the key factors that dictate the eventual outcome. Bilateral cochlear implantation in children and combined electro-acoustic stimulation are the new developments in this field of rehabilitation for the deaf. Pakistan Cochlear Implant Programme was started in year 2000 and one hundred and fifty subjects have undergone cochlear implant surgery so far at Karachi, Lahore and Peshawar since. This prospective study was designed to evaluate the development of auditory perception skills and language in children, over a twelve months period, following cochlear implantation. METHODS: Twenty-one patients were enrolled in this evaluation. These were divided into three groups as per age factor. Group 1 included eleven children of ages less than five years, Group 2 included eight children of ages between five and nine years whereas, Group 3 included two eleven years old children. Furthermore, subjects in Group 1 & 2 were pre-lingual whereas those in Group 3 were post-lingual. The three groups were evaluated using "Evaluation of Auditory Responses to Speech" (EARS). RESULTS: Improvement in performance on all measures was noticed in all the groups over a twelve months period following implantation. Dynamics of improvement in auditory skills suggested more and rapid development in younger age group. CONCLUSION: Children of varying ages, both pre and post lingual, did show improvement in the development of auditory perception skills, that was evident more in the younger age group.

17ß-Estradiol via SIRT1/Acetyl-p53/NF-kB Signaling Pathway Rescued Postnatal Rat Brain Against Acute Ethanol Intoxication.

Growing evidences reveal that 17ß-estradiol has a wide variety of neuroprotective potential. Recently, it has been shown that 17ß-estradiol can limit ethanol-induced neurotoxicity in neonatal rats. Whether it can stimulate SIRT1 signaling against ethanol intoxicity in developing brain remain elusive. Here, we report for the first time that 17ß-estradiol activated SIRT1 to deacetylate p53 proteins against acute ethanol-induced oxidative stress, neuroinflammation, and neurodegeneration. A single subcutaneous injection of ethanol-induced oxidative stress triggered phospho c-jun N terminal kinase (p-JNK) and phospho mammalian target of rapamycin (p-mTOR) accompanied by neuroinflammation and widespread neurodegeneration. In contrast, 17ß-estradiol cotreatment positively regulated SIRT1, inhibited p53 acetylation, reactive oxygen species (ROS) production, p-JNK, and p-mTOR activation and reduced neuroinflammation and neuronal cell death in the postnatal rat brain. Interestingly, SIRT1 inhibition with its inhibitor, i.e., EX527 further enhanced ethanol intoxication and also abolished the beneficial effects of 17ß-estradiol against ethanol in the young rat's brain. Indeed, 17ß-estradiol treatment increased the cell viability (HT22 cells), inhibited ROS production via the SIRT1/Acetyl-p53 pathway, and reduced the nuclear translocation of phospho-nuclear factor kappa B (p-NF-kB) in the BV2 microglia cells. Taken together, these results show that 17ß-estradiol can be used as a potential neuroprotective agent against acute ethanol intoxication.