Oral Administration of a Specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairs Spinal Cord Injury.

TTK21 is a small-molecule activator of p300/creb binding protein (CBP) acetyltransferase activity, which, upon conjugation with a glucose-derived carbon nanosphere (CSP), can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory following intraperitoneal (IP) administration is well established. In this study, we successfully demonstrate that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigate the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice and evaluate their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits efficacy equivalent to that of IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor function, histone acetylation dynamics, and increased expression of regeneration-associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Importantly, no toxic and mutagenic effects of CSP-TTK21 are observed at a maximum tolerated dose of 1 g/kg in Sprague-Dawley (SD) rats via the oral route. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.

Anti-amyloidogenic amphipathic arginine-dehydrophenylalanine spheres capped selenium nanoparticles as potent therapeutic moieties for Alzheimer's disease.

Aggregation of both amyloid beta (Aß) peptide and hyperphosphorylated tau proteins is the major pathological hallmark of Alzheimer's disease (AD). Moieties that carry anti-amyloidogenic potency against both of the aggregating entities are considered to be promising drug candidatures for the disease. In the current work, we have synthesized amphipathic dipeptide vesicle-templated selenium nanoparticles (RΔF-SeNPs) as potential entities to combat AD. We have investigated and established their anti-amyloidogenic activity against different peptide-based amyloid models, such as the reductionist model based on the dipeptide phenylalanine-phenylalanine (FF) derived from Aß; a model based on the hexapeptide Ac-PHF6 (306VQIVYK311) derived from tau protein; and the full-length Aß42 polypeptide-based model. We also evaluated the neuroprotective characteristics of RΔF-SeNPs against FF, Ac-PHF6, and Aß42 fibril-induced toxicity in neuroblastoma, SH-SY5Y cells. RΔF-SeNPs further exhibited neuroprotective effects in streptozotocin (STZ) treated neuronal (N2a) cells carrying AD-like features. In addition, studies conducted in an intra-cerebroventricular STZ-instigated rat model of dementia revealed that RΔF-SeNP-treated animals showed improved cognitive activity and reduced Aß42 aggregate burden in brain tissues as compared with the STZ-treated group. Moreover, in vivo brain distribution studies conducted in animal models additionally demonstrated the brain-homing ability of RΔF-SeNPs. All together, these studies supported the potency of RΔF-SeNPs as efficient and propitious disease-modifying therapeutic agents for combating AD.

Caffeine improves memory and cognition via modulating neural progenitor cell survival and decreasing oxidative stress in Alzheimer's rat model.

AIMS: Caffeine possesses potent antioxidant, anti-inflammatory and anti-apoptotic activities against a variety of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The goal of this study was to investigate the protective role of a psychoactive substance like caffeine on hippocampal neurogenesis and memory functions in streptozotocin (STZ)-induced neurodegeneration in rats. BACKGROUND: Caffeine is a natural CNS stimulant, belonging to the methylxanthine class, and is a widely consumed psychoactive substance. It is reported to abate the risk of various abnormalities that are cardiovascular system (CVS) related, cancer related, or due to metabolism dysregulation. Short-term caffeine exposure has been widely evaluated, but its chronic exposure is less explored and pursued. Several studies suggest a devastating role of caffeine in neurodegenerative disorders. However, the protective role of caffeine on neurodegeneration is still unclear. OBJECTIVE: Here, we examined the effects of chronic caffeine administration on hippocampal neurogenesis in intracerebroventricular STZ injection induced memory dysfunction in rats. The chronic effect of caffeine on proliferation and neuronal fate determination of hippocampal neurons was evaluated by co-labeling of neurons by thymidine analogue BrdU that labels new born cells, DCX (a marker for immature neurons) and NeuN that labels mature neurons. METHOD: STZ (1 mg/kg, 2 µl) was injected stereotaxically into the lateral ventricles (intracerebroventricular injection) once on day 1, followed by chronic treatment with caffeine (10 mg/kg, i.p) and donepezil (5 mg/kg, i.p.). Protective effect of caffeine on cognitive impairment and adult hippocampal neurogenesis was evaluated. RESULT: Our findings show decreased oxidative stress burden and amyloid burden following caffeine administration in STZ lesioned SD rats. Further, double immunolabeling with bromodeoxyuridine+/doublecortin+ (BrdU+/DCX+) and bromodeoxyuridine+/ neuronal nuclei+ (BrdU+/NeuN+) has indicated that caffeine improved neuronal stem cell proliferation and long term survival in STZ lesioned rats. CONCLUSION: Our findings support the neurogenic potential of caffeine in STZ induced neurodegeneration.

Crosstalk between Adult Hippocampal Neurogenesis and Its Role in Alzheimer's Disease.

The functional and developmental unit of neurogenesis is neural stem cells (NSCs). These NSCs have self-renewal capacity and produce new neurons throughout life in different neurogenic niche. Neurogenesis in adult brain is associated with synaptic plasticity, learning, and memory in dentate gyrus (DG) of hippocampus and olfactory bulb. Remarkably, weakened neurogenesis has been viewed before the onset of different pathological hallmarks of neurological disorders. In this review, we have provided evidence which implicates impaired neurogenesis as a culprit in age associated neurological disorders with greater emphasis on Alzheimer's disease (AD). Moreover, an insight about the molecular and cellular regulation linked with altered neurogenesis in young and aging brain has also been discussed. This review further summarizes the therapeutic strategies for targeting the manipulation of the neural stem cell pool and factors affecting the pool involved in AD.

ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes.

Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca2+ influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.

Lipidomics and proteomics: An integrative approach for early diagnosis of dementia and Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and considered to be responsible for majority of worldwide prevalent dementia cases. The number of patients suffering from dementia are estimated to increase up to 115.4 million cases worldwide in 2050. Hence, AD is contemplated to be one of the major healthcare challenge in current era. This disorder is characterized by impairment in various signaling molecules at cellular and nuclear level including aggregation of Aß protein, tau hyper phosphorylation altered lipid metabolism, metabolites dysregulation, protein intensity alteration etc. Being heterogeneous and multifactorial in nature, the disease do not has any cure or any confirmed diagnosis before the onset of clinical manifestations. Hence, there is a requisite for early diagnosis of AD in order to downturn the progression/risk of the disorder and utilization of newer technologies developed in this field are aimed to provide an extraordinary assistance towards the same. The lipidomics and proteomics constitute large scale study of cellular lipids and proteomes in biological matrices at normal stage or any stage of a disease. The study involves high throughput quantification and detection techniques such as mass spectrometry, liquid chromatography, nuclear mass resonance spectroscopy, fluorescence spectroscopy etc. The early detection of altered levels of lipids and proteins in blood or any other biological matrices could aid in preventing the progression of AD and dementia. Therefore, the present review is designed to focus on the recent techniques and early diagnostic criteria for AD, revealing the role of lipids and proteins in this disease and their assessment through different techniques.

Activation of Angiotensin-converting Enzyme 2 Protects Against Lipopolysaccharide-induced Glial Activation by Modulating Angiotensin-converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis.

Neuroinflammation is associated with activation of glial cells and pro-inflammatory arm of the central Renin Angiotensin System (RAS) namely, Angiotensin-Converting Enzyme/Angiotensin II/Angiotensin Type 1 Receptor (ACE/Ang II/AT1R) axis. Apart from this, another axis of RAS also exists, Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR), which counters ACE/Ang II/AT1R axis by showing anti-inflammatory properties. However, the role of ACE2/Ang (1-7)/MasR axis has not been explored in glial activation and neuroinflammation. Hence, the present study tries to unveil the role of ACE2/Ang (1-7)/MasR axis in lipopolysaccharide (LPS)-induced neuroinflammation using diminazene aceturate (DIZE), an ACE2 activator, in astroglial (C6) and microglial (BV2) cells as well as male SD rats. We found that ACE2 activation efficiently prevented LPS-induced changes by decreasing glial activation, inflammatory signaling, cell migration, ROS generation via upregulation of ACE2/Ang (1-7)/MasR signaling. In addition, activation of ACE2/Ang (1-7)/MasR axis by DIZE significantly suppressed the pro-inflammatory ACE/Ang II/AT1R axis by reducing Ang II level in neuroinflammatory conditions induced by LPS in both in vitro and in vivo. ACE2/Ang (1-7)/MasR axis activation further decreased mitochondrial depolarization and apoptosis, hence providing neuroprotection. Furthermore, to validate that the beneficial effect of the ACE2 activator was indeed through MasR, a selective MasR antagonist (A779) was used that significantly blocked the anti-inflammatory effect of ACE2 activation by DIZE. Hence, our study demonstrated that ACE2 activation imparted neuroprotection by enhancing ACE2/Ang (1-7)/MasR signaling which in turn decreased glial activation, neuroinflammation, and apoptosis and improved mitochondrial health.

Angiotensin-Converting Enzyme 2 Activation Mitigates Behavioral Deficits and Neuroinflammatory Burden in 6-OHDA Induced Experimental Models of Parkinson's Disease.

Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both in vitro as well as in vivo models of PD. DIZE exerted its effect by activating ACE2 that produced Ang (1-7), a neuroprotective peptide. Ang (1-7) conferred its neuroprotective effect upon binding with the G-protein-coupled MAS receptor that led to the upregulation of cell survival proteins while downregulating apoptotic proteins. Importantly, these findings were further validated by using A-779, a MasR antagonist. The result showed that treatment with A-779 reversed the antioxidative and anti-inflammatory effects of DIZE by decreasing glial activation and neuroinflammatory markers. Although the role of ACE2 in PD pathology needs to be additionally confirmed using transgenic models in either ACE2 overexpressing or knockout mice, still, our study demonstrates that enhancing ACE2 activity could be a novel approach for ameliorating PD pathology.

Self-Fluorescent Lone Tryptophan Nanoparticles as Theranostic Agents Against Alzheimer's Disease.

Aggregation of ß-amyloid (Aß42) peptide in the neural extracellular space leads to cellular dysfunction, resulting in Alzheimer's disease (AD). The hydrophobic core of the amyloidogenic Aß42 peptide contains aromatic residues that play an important role in the self-assembly and subsequent aggregation of the peptide. Hence, targeting these hydrophobic core residues by potent low molecular agents can be a promising therapeutic approach toward AD. In the current work, we have developed self-fluorescent solo tryptophan nanoparticles (TNPs) as nanotheranostic systems against AD. We demonstrated that TNPs could significantly inhibit as well as disrupt the fibrils formed by both Aß42 peptide and another reductionist approach-based amyloid model dipeptide, phenylalanine-phenylalanine (FF). More importantly, these nanostructures were nontoxic to neural cells and could protect the neurons from Aß42 peptide and FF aggregate-induced cytotoxicity. In addition, efficacy studies performed in animal model further revealed that the TNPs could rescue spatial and learning memory in intracerebroventricular streptozotocin-administration-induced AD phenotype in rats. Moreover, our pharmacokinetics study further established the BBB permeability and brain delivery potency of TNPs. The inherent excellent fluorescent properties of these nanoparticles could be exploited further to use them as imaging modalities for tagging and detecting FF and Aß42 peptide fibrils. Overall, our results clearly illustrated that the solo TNPs could serve as promising nanotheranostic agents for AD therapy.

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation.

AIMS: Isoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat. MAIN METHODS: Four groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation. KEY FINDINGS: The modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL2) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1ß and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions. SIGNIFICANCE: The aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.

Regulatory safety pharmacology and toxicity assessments of a standardized stem extract of Cassia occidentalis Linn. in rodents.

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.

Chronic unpredictable stress negatively regulates hippocampal neurogenesis and promote anxious depression-like behavior via upregulating apoptosis and inflammatory signals in adult rats.

Psychological and physical stress play a pivotal role in etiology of anxiety and depression. Chronic psychological and physical stress modify various physiological phenomena, as a consequence of which oxidative stress, decreased neurotransmitter level, elevated corticosterone level and altered NSC homeostasis is observed. However, the precise mechanism by which chronic stress induce anxious depression and modify internal milieu is still unknown. Herein, we show that exposure to CUS increase oxidative stress, microgliosis, astrogliosis while it reduces hippocampal NSC proliferation, neuronal differentiation and maturation in adult rats. CUS exposure in rats reduce dopamine and serotonin level in cortex and hippocampus, which result in increased anxiety and depression-like phenotypes. We also found elevated level of NF-κB and TNF-α while decreased anti-inflammatory cytokine IL-10 level, that led to increased expression of Bax and cleaved Caspase-3 whereas down regulation of antiapoptotic protein Bcl2. Additionally, CUS altered adult hippocampal neurogenesis, increased gliosis and neuronal apoptosis in cerebral cortex and hippocampus which might be associated with reduced AKT and increased ERK signaling, as seen in the rat brain tissue. Taken together, these results indicate that CUS induce oxidative stress and neuroinflammation which directly affects NSC dynamics, monoamines levels and behavioral functions in adult rats.

Protriptyline improves spatial memory and reduces oxidative damage by regulating NFκB-BDNF/CREB signaling axis in streptozotocin-induced rat model of Alzheimer's disease.

Antidepressants are well known to exert their role via upregulation of brain derived neurotrophic factor (BDNF). BDNF has been reported to exerts its neuroprotective effect in rodent and primate models as well as in patients of Alzheimer's disease (AD). The aim of our study was to evaluate the effect of protriptyline (PRT), a tricyclic antidepressant, in streptozotocin (STZ)- induced rat model of AD. Total 10 µl of STZ was injected into each ventricle (1 mg/kg). PRT (10 mg/kg, i.p.) treatment was started 3-day post STZ administration and continued till 21 days. We found that STZ treatment significantly increased pTau, Aß42 and BACE-1 expression, oxidative stress and neurodegeneration in hippocampus and cortex of adult rats. STZ induced impairment in spatial learning and retention memory was associated with increased NFκB and reduced CREB and BDNF expression in cortex and hippocampus. Interestingly, PRT treatment significantly reduced pTau, Aß42 and BACE-1 levels, neurodegeneration, oxidative stress and glial activation, contributing to the improved spatial learning and retention memory in STZ treated rats. Moreover, PRT treatment significantly improved p-ERK/ERK ratio and enhanced BDNF and CREB levels by reducing NFκB and GFAP expression in STZ treated rats. Our data suggest that impaired NFκB and CREB signaling potentially contribute in AD pathogenesis by elevating oxidative stress and neuroinflammation mediated neurodegeneration. Our study has established protriptyline as a multi target molecule in pre-clinical model of AD and further investigations on PRT like molecules could pave way for further development of effective new treatments in neurodegenerative disorders.

Fluorescent Dopamine-Tryptophan Nanocomposites as Dual-Imaging and Antiaggregation Agents: New Generation of Amyloid Theranostics with Trimeric Effects.

The aggregation of neurotoxic amyloid-ß (Aß) polypeptides into aberrant extracellular senile plaques is the major neuropathological hallmark of Alzheimer's disease (AD). Inhibiting aggregation of these peptides to control the progression of this deadly disease can serve as a viable therapeutic option. In the current work, inherently fluorescent theranostic dopamine-tryptophan nanocomposites (DTNPs) were developed and investigated for their amyloid inhibition propensity along with their ability to act as a cellular bioimaging agent in neuronal cells. The antiaggregation potency of the nanocomposites was further investigated against an in vitro established reductionist amyloid aggregation model consisting of a mere dipeptide, phenylalanine-phenylalanine (FF). As opposed to large peptide/protein-derived robust and high-molecular-weight amyloid aggregation models of Alzheimer's disease, our dipeptide-based amyloid model provides an edge over others in terms of the ease of handling, synthesis, and cost-effectiveness. Results demonstrated positive antiaggregation behavior of the DTNPs toward both FF-derived amyloid fibrils and preformed Aß-peptide fibers by means of electron microscopic and circular dichroism-based studies. Our results further pointed toward the neuroprotective effects of the DTNPs in neuroblastoma cells against FF amyloid fibril-induced toxicity and also that they significantly suppressed the accumulation of Aß42 oligomers in both cortex and hippocampus regions and improved cognitive impairment in an intracerebroventricular streptozotocin (ICV-STZ)-induced animal model of dementia. Besides, DTNPs also exhibited excellent fluorescent properties and light up the cytoplasm of neuroblastoma cells when being coincubated with cells, confirming their ability to serve as an intracellular bioimaging agent. Overall, these results signify the potency of the DTNPs as promising multifunctional theranostic agents for treating AD.

Mechanistic exploration of quercetin against metronidazole induced neurotoxicity in rats: Possible role of nitric oxide isoforms and inflammatory cytokines.

AIM: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin. MAIN METHODS: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl2, iNOS, eNOS and caspase-3. KEY FINDINGS: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers. SIGNIFICANCE: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.

Dopamine D1 receptor agonism induces dynamin related protein-1 inhibition to improve mitochondrial biogenesis and dopaminergic neurogenesis in rat model of Parkinson's disease.

Dopamine (DA) neurotransmitter act on dopamine receptors (D1-D5) to regulate motor functions, reward, addiction and cognitive behavior. The depletion of DA in midbrain due to degeneration of nigral dopaminergic (DAergic) neurons leads to Parkinson's disease (PD). DA agonist and levodopa (L-DOPA) are the only therapies used for symptomatic relief in PD. However, the role of DA receptors in PD pathogenesis and how they are associated with mitochondrial functions and DAergic neurogenesis is still not known. Here, we investigated the mechanistic aspect of DA D1 receptor mediated control of DAergic neurogenesis, motor behavior and mitochondrial functions in rat PD model. The pharmacological activation of D1 receptors markedly improved motor deficits, mitochondrial biogenesis, ATP levels, mitochondrial membrane potential and defended nigral DAergic neurons against 6-hydroxydopamine (6-OHDA) induced neurotoxicity in adult rats. However, the D1 agonist mediated effects were abolished following D1 receptor antagonist treatment in 6-OHDA lesioned rats. Interestingly, pharmacological inhibition of dynamin related protein-1 (Drp-1) by Mdivi-1 in D1 antagonist treated PD rats, significantly restored behavioral deficits, mitochondrial functions, mitochondrial biogenesis and increased the number of newborn DAergic neurons in substantia nigra pars compacta (SNpc). Drp-1 inhibition mediated neuroprotective effects in PD rats were associated with increased level of protein kinase-B/Akt and extracellular-signal-regulated kinase (ERK). Taken together, our data suggests that dopamine D1 receptor mediated reduction in mitochondrial fission and enhanced DAergic neurogenesis may involve Drp-1 inhibition which led to improved behavioral recovery in PD rats.

Enhanced neuroinflammation and oxidative stress are associated with altered hippocampal neurogenesis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice.

Loss of midbrain dopaminergic neurons in Parkinson's disease not only induces motor impairments but also leads to the development of non-motor symptoms such as memory impairment, anxiety and depression. Dopaminergic axons directly innervate hippocampus and release dopamine in the local environment of hippocampus, and hence are directly involved in the modulation of hippocampal-dependent functions. Studies have explored the potential effect of dopamine on adult hippocampal neurogenesis. However, it is not well defined whether oxidative damage and inflammation could be associated with alteration in adult hippocampal neurogenesis. In the present study, we analyzed the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on adult hippocampal neurogenesis and how it is associated with inflammatory conditions in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease-like phenotypes. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice exhibited significantly reduced dopaminergic neurons and dopamine content that resulted in impairment of motor functions. Interestingly, the formation of endogenous neuronal precursor cells and the number of neuroblasts in the hippocampus were significantly increased following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. Net hippocampal neurogenesis was also reduced in the hippocampus after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. These effects in the hippocampus were associated with increased oxidative stress markers and a massive reactive gliosis. Taken together, our results suggest that degeneration of midbrain dopaminergic neurons directly affects the local hippocampal microenvironment by enhancing inflammatory influences. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammatory reaction in the hippocampus may alter the endogenous regenerative capacity of the brain. Therefore, anti-inflammatory agents could be a potential therapy for the improvement of the endogenous regenerative capacity of the aging or neurodegenerative brain.

Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: A role of Wnt signalling.

Nigral dopaminergic (DAergic) cell degeneration and depletion of dopamine neurotransmitter in the midbrain are cardinal features of Parkinson's disease (PD). Dopamine system regulates different aspects of behavioural phenotypes such as motor control, reward, anxiety and depression via acting on dopamine receptors (D1-D5). Recent studies have shown the potential effects of dopamine on modulation of neurogenesis, a process of newborn neuron formation from neural stem cells (NSCs). Reduced proliferative capacity of NSCs and net neurogenesis has been reported in subventricular zone, olfactory bulb and hippocampus of patients with PD. However, the molecular and cellular mechanism of dopamine mediated modulation of DAergic neurogenesis is not defined. In this study, we attempted to investigate the molecular mechanism of dopamine receptors mediated control of DAergic neurogenesis and whether it affects mitochondrial biogenesis in 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes. Unilateral administration of 6-OHDA into medial forebrain bundle potentially reduced tyrosine hydroxylase immunoreactivity, dopamine content in substantia nigra pars compacta (SNpc) and striatum region and impaired motor functions in adult rats. We found decreased D1 receptor expression, mitochondrial biogenesis, mitochondrial functions and DAergic differentiation associated with down-regulation of Wnt/ß-catenin signalling in SNpc of 6-OHDA lesioned rats. Pharmacological stimulation of D1 receptor enhanced mitochondrial biogenesis, mitochondrial functions and DAergic neurogenesis that lead to improved motor functions in 6-OHDA lesioned rats. D1 agonist induced effects were attenuated following administration of D1 antagonist, whereas shRNA mediated knockdown of Axin-2, a negative regulator of Wnt signalling significantly abolished D1 antagonist induced impairment in mitochondrial biogenesis and DAergic neurogenesis in 6-OHDA lesioned rats. Our results suggest that dopamine receptor regulates DAergic neurogenesis and mitochondrial functions by activation of Wnt/ß-catenin signaling in rat model of PD-like phenotypes.

Acceptability of Mental Health Facilities and De-addiction Centers in India.

Not much is known about disease prevalence, treatment outcomes, trained manpower, programs, and patients' awareness of diseases from South Asia, compared with the Western world. While other aspects are improving, the quantitative evaluation of awareness of diseases is lagging. Compared with other diseases, the situation for mental health disorders and addiction is worse. While no single study can fully quantify all aspects of awareness, a good starting point is to understand if increasing the number of mental health facilities is beneficial by understanding people's perception toward the likelihood of contracting various diseases, their preferred approach to treatment, and their perception of whether there are enough current facilities. We surveyed over 8000 families across several states of India and asked if they would treat a particular problem at home, visit a local healer, seek religious council, or go to a modern hospital for treatment. Our questions also included non-medical options to assess how likely people are to avoid trained medical help. We also asked people about their perceived likelihood of a family member ever suffering from (1) diarrhea, (2) high fever, (3) alcoholism, and (4) schizophrenia and other mental health problems. We reversed the order of diseases in our questions for a fraction of the population to evaluate the effect of order of questioning. Finally, we asked, if people feel they have enough local healers, religious places, general hospitals, de-addiction centers, and mental health facilities. Despite the taboo around mental health, many people claimed that their family members were unlikely to contract mental health or addiction problems, people recognized the severe paucity of mental health facilities and de-addiction centers. This raises hope for improving the mental health situation in India. We also found a significant relation between education levels and choices people make, underscoring the positive role education has in improving mental health.