Spermidine as an epigenetic regulator of autophagy in neurodegenerative disorders.

Autophagy is an abnormal protein degradation and recycling process that is impaired in various neurological diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Spermidine is a natural polyamine found in various plant- and meat-based diets that can induce autophagy and is decreased in various neurodegenerative diseases. It acts on epigenetic enzymes like E1A-binding protein p300, HAT enzymes like Iki3p and Sas3p, and α-tubulin acetyltransferase 1 that modulate autophagy. Histone modifications like acetylation, phosphorylation, and methylation could influence autophagy. Autophagy is epigenetically regulated in various neurodegenerative disorders with many epigenetic enzymes and miRNAs. Polyamine regulation plays an essential role in the disease pathogenesis of AD and PD. Therefore, in this review, we discuss various enzymes and miRNAs involved in the epigenetic regulation of autophagy in neurodegenerative disorders and the role of spermidine as an autophagy enhancer. The alterations in spermidine-mediated regulation of Beclin-1, LC3-II, and p62 genes in AD and other PD-associated enzymes could impact the process of autophagy in these neurodegenerative diseases. With the ever-growing data and such promising effects of spermidine in autophagy, we feel it could be a promising target in this area and worth further detailed studies.

Involvement of NLRP3 inflammasome pathway in the protective mechanisms of ferulic acid and p-coumaric acid in LPS-induced sickness behavior and neuroinflammation in mice.

Ferulic acid (FA) and p-coumaric acid (PCA) are abundantly present in commonly consumed food and beverages. Being polyphenolic compounds, they have been explored for their antioxidant and anti-inflammatory properties. Based on our previous study, we selected these two compounds to further investigate their potential in lipopolysaccharide (LPS)-induced sickness behavior and the ensuing neuroinflammation by specifically focusing on the NLRP3 inflammasome pathway. Male Swiss albino mice were divided into nine groups (n = 6) consisting of Normal Control, LPS, fluoxetine (FLX), FA40, FA160, FA640, PCA40, PCA160, and PCA640 respectively. Each group received respective FA or PCA treatment except Normal Control and LPS, which received the vehicle, carboxymethylcellulose 0.25% w/v. All groups were challenged with LPS 1.5 mg/kg, intraperitoneally except the Normal Control group, which received saline. Behavioral assessments were performed between 1-2 h, and the whole brains were collected at 3 h post-LPS administration. LPS-induced sickness behavior was characterized by significantly reduced spontaneous activity and high immobility time. The expression of NLRP3, ASC, caspase-1 and IL-1ß was significantly increased, along with the levels of brain IL-1ß suggesting the assembly and activation of NLRP3 inflammasome pathway. Furthermore, the major cytokines involved in sickness behavior, IL-6 and TNF-α were also significantly elevated with the accompanied lipid peroxidation. The results of this study emphasize that within the employed dose ranges of both FA and PCA, both the compounds were effective at blocking the activation of the NLRP3 inflammasome pathway and thereby reducing the release of IL-1ß and the sickness behavior symptoms. There was a prominent effect on cytokine levels and lipid peroxidation as well.

Evaluating the Role of N-Acetyl-L-Tryptophan in the Aß 1-42-Induced Neuroinflammation and Cognitive Decline in Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative condition previously known to affect the older population, is also now seen in younger individuals. AD is often associated with cognitive decline and neuroinflammation elevation primarily due to amyloid ß (Aß) accumulation. Multiple pathological complications in AD call for therapies with a wide range of neuroprotection. Our study aims to evaluate the effect of N-acetyl-L-tryptophan (NAT) in ameliorating the cognitive decline and neuroinflammation induced by Aß 1-42 oligomers and to determine the therapeutic concentration of NAT in the brain. We administered Aß 1-42 oligomers in rats via intracerebroventricular (i.c.v.) injection to induce AD-like conditions. The NAT-treated animals lowered the cognitive decline in the Morris water maze characterized by shorter escape latency and increased path efficiency and platform entries. Interestingly, the hippocampus and frontal cortex showed downregulation of tumor necrosis factor, interleukin-6, and substance P levels. NAT treatment also reduced acetylcholinesterase activity and total and phosphorylated nuclear factor kappa B and Tau levels. Lastly, we observed upregulation of cAMP response element-binding protein 1 (CREB1) signaling. Surprisingly, our HPLC method was not sensitive enough to detect the therapeutic levels of NAT in the brain, possibly due to NAT concentrations being below the lowest limit of quantification of our validated method. To summarize, the administration of NAT significantly lowered cognitive decline, neuroinflammatory pathways, and Tau protein and triggered the upregulation of CREB1 signaling, suggesting its neuroprotective role in AD-like conditions.

Involvement of indoleamine 2, 3-dioxygenase (IDO) and brain-derived neurotrophic factor (BDNF) in the neuroprotective mechanisms of ferulic acid against depressive-like behaviour.

OBJECTIVE: Ferulic acid (FA) is a common food ingredient that is abundantly present in various routinely consumed food and beverages. Like many cinnamic acid derivatives, FA produces wide-ranging effects in a dose-dependent manner and various studies link FA consumption with reduced risk of depressive disorders. The aim of this study was to exploit the neuroprotective mechanisms of FA including indoleamine 2,3-dioxygenase (IDO), brain-derived neurotrophic factor (BDNF), and other pro-inflammatory cytokines by employing lipopolysaccharide (LPS)-induced depressive-like behaviour model. METHODS: C57BL/6J male mice were divided into 4 groups consisting of saline (SAL), LPS, FA and Imipramine (IMI). Animals were pretreated orally with FA (10 mg/kg) and IMI (10 mg/kg) for 21 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 21. RESULTS: LPS administration produced a biphasic change in the behaviour of the animals where the animals lost a significant weight and express high immobility time at 24 h. Proinflammatory cytokines including, TNF-α, IL-6, IL-1ß, and IFN-γ were significantly increased along with increased lipid peroxidation and reduced BDNF. Furthermore, the increased kynurenine to tryptophan ratio was indicative of elevated IDO activity. CONCLUSION: The results of this study emphasise that low dose of FA is effective in attenuating depressive-like behaviour by modulating IDO, BDNF and reducing neuroinflammation.

Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a chronic incapacitating condition with recurrent experience of trauma-related memories, negative mood, altered cognition, and hypervigilance. Agglomeration of preclinical and clinical evidence in recent years specified that alterations in neural networks favor certain characteristics of PTSD. Besides the disruption of hypothalamus-pituitary-axis (HPA) axis, intensified immune status with elevated pro-inflammatory cytokines and arachidonic metabolites of COX-2 such as PGE2 creates a putative scenario in worsening the neurobehavioral facet of PTSD. This review aims to link the Diagnostic and Statistical Manual of mental disorders (DSM-V) symptomology to major neural mechanisms that are supposed to underpin the transition from acute stress reactions to the development of PTSD. Also, to demonstrate how these intertwined processes can be applied to probable early intervention strategies followed by a description of the evidence supporting the proposed mechanisms. Hence in this review, several neural network mechanisms were postulated concerning the HPA axis, COX-2, PGE2, NLRP3, and sirtuins to unravel possible complex neuroinflammatory mechanisms that are obscured in PTSD condition.

Dopaminergic Signaling as a Plausible Modulator of Astrocytic Toll-Like Receptor 4: A Crosstalk between Neuroinflammation and Cognition.

Neuroinflammation is one of the major pathological factors leading to Alzheimer's disease (AD). The role of microglial cells in neuroinflammation associated with AD has been known for a long time. Recently, astrocytic inflammatory responses have been linked to the neuronal degeneration and pathological development of AD. Lipopolysaccharide (LPS) and Amyloid Beta (Aß) activate astrocytes and microglial cells via toll-like 4 (TLR4) receptors leading to neuroinflammation. Reactive (activated) astrocytes mainly comprising of A1 astrocytes (A1s) are involved in neuroinflammation, while A2 astrocytes (A2s) possess neuroprotective activity. Studies link low dopamine (DA) levels during the early stages of neurodegenerative disorders with its anti-inflammatory and immuoregulatory properties. DA mediates neuroprotection via inhibition of the A1 astrocytic pathway through blockade of NF-kB and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3); and promotion of A2 astrocytic pathways leading to the formation of neurotrophic factors like BDNF and GDNF. In this current review, we have discussed the crosstalk between the dopaminergic system in astrocytic TLR4 and NF-kB in addition to NLRP3 inflammasome in the modulation of neuroinflammatory pathologies in cognitive deficits.

Avanafil mediated dual inhibition of IKKß and TNFR1 in an experimental paradigm of Alzheimer's disease: in silico and in vivo approach.

In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-ß kinase subunit ß (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aß), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aß levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aß , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.

Putative involvement of sirtuin modulators in LPS-induced sickness behaviour in mice.

NAD+-dependent histone deacetylases (sirtuins 1-7) have been shown to be involved in various pathophysiological conditions including their involvement in cardiovascular, cancerous, neurodegenerative, immune dysregulation and inflammatory conditions. This study investigates the inflammomodulatory potential of resveratrol (RES), a sirtuin activator and sirtinol (SIR), a sirtuin inhibitor in lipopolysaccharide (LPS)-induced model of sickness behaviour in mice. Male Swiss albino mice were divided into five groups (n = 6) consisting of saline (SAL), LPS, RES, SIR, and fluoxetine (FLU) respectively, each group except LPS was prepared by intraperitoneally (i.p.) administration of SAL (10 mL/kg), RES (50 mg/kg), SIR (2 mg/kg) and FLU (10 mg/kg). Thirty minutes after the treatments, all the groups, except SAL were administered LPS (2 mg/kg, i.p.). The behavioural assays including, open field test, forced swim test, and tail suspension tests were conducted 1 h after LPS challenge. LPS administration significantly reduced the locomotor activity along with inducing a state of high immobility and that was prevented by pretreatment with RES and SIR. Further, various proinflammatory cytokines (TNF-α, IL-6, and IL-1ß), and oxidative stress markers (MDA and GSH) were found to be significantly elevated in the brain homogenates after LPS treatment. SIR pretreatment abrogated the LPS-induced neuroinflammatory and oxidative stress changes, whereas RES was only effective in reducing the oxidative stress and TNF-α levels. The results of this study speculate that the role of SIRT modulators in neuroinflammatory conditions could vary with their dose, regimen and chemical properties. Further studies with detailed molecular and pharmacokinetic profiling will be needed to explore their therapeutic potentials.

Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders.

Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value.

Reviewing the importance of TLR-NLRP3-pyroptosis pathway and mechanism of experimental NLRP3 inflammasome inhibitors.

Cells encounter continuous challenges due to tissue insult caused by endogenous and/or exogenous stimuli. Among the mechanisms set in place to counterbalance the tissue insult, innate immunity is always at the forefront. Cells of innate immunity efficiently recognize the 'danger signals' via a specialized set of membrane-bound receptors known as Toll-like receptors. Once this interaction is established, toll-like receptor passes on the responsibility to cytosolic NOD-like receptors through a cascade of signalling pathways. Subsequently, NOD-like receptors assemble to a specialized multiprotein intracellular complex, that is inflammasome. Inflammasome activates Caspase-1 and Gasdermin-D which initiate pyroptotic cell death in the affected tissue by two simultaneous mechanisms. Being a protease, caspase-1 cleaves and activates pro-inflammatory cytokines IL-1ß and IL-18. On the other hand, Gasdermin-D causes proteolytic cleavage which forms a pore in the cell membrane. This review highlights the molecular events ranging from recognition of stimuli to pyroptosis. The review is also an attempt to discuss the mechanisms of the most specific experimental NLRP3 inhibitors.

Remedial effects of caffeine against depressive-like behaviour in mice by modulation of neuroinflammation and BDNF.

Objective: Caffeine (CAF) is one of the most commonly consumed nutritional stimulant in beverages. Interestingly, CAF produces varied effects in a dose-dependent manner, and that makes it one of the most controversial nutritional ingredients. Various studies have linked CAF consumption and reduced risk of depressive disorders. The aim of this study was to investigate the effect of CAF on lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviour.Methods: C57BL/6J male mice were divided into four groups consisting of saline (SAL), LPS, CAF and Imipramine (IMI). Animals were pretreated orally with CAF (10 mg/kg) and IMI (10 mg/kg) for 14 days once daily and all groups except SAL were challenged with LPS (0.83 mg/kg) intraperitoneally on day 14.Results: LPS produced a biphasic behavioural response with a significantly high immobility time and weight loss after 24 h. The brain cytokines (TNF-α, IL-6, IL-1ß, and IFN-γ) levels were remarkably high, along with increased lipid peroxidation and reduced Brain Derived Neurotrophic Factor (BDNF). These biochemical and behavioural changes were significantly alleviated by CAF and IMI chronic treatment.Conclusion: The results of this study implicate that mild-moderate consumption of CAF could impart anti-inflammatory properties under neuroinflammatory conditions by modulating the cytokine and neurotrophic mechanisms.

Sirtuins, a potential target in Traumatic Brain Injury and relevant experimental models.

Traumatic brain injury (TBI) can simply be defined as a violent external injury to the head causing brain dysfunction. The primary injury occurs immediately on impact whereas the secondary injury begins minutes to months after impact. TBI affects a vast majority of population worldwide yet, there isn't any therapeutic intervention available. Sirtuins (SIRTs) are important regulator proteins found in humans. In several neurodegenerative diseases, SIRTs have proven its neuroprotective actions. Owing to the pathophysiological similarities in these diseases and TBI, SIRTs may serve as a potential target for therapeutic intervention in TBI. This review aims to describe the relevance of SIRTs as a potential pharmacological target in TBI. Also, the experimental animal model of TBI explored to understand the role of SIRTs in TBI have been discussed.

Inhibition of NLRP3-inflammasome mediated IL-1ß release by phenylpropanoic acid derivatives: in-silico and in-vitro approach.

NLRP3 inflammasome activation and subsequent release of IL-1ß are being explored as a causal pathology for inflammatory and autoimmune disorders. Modulation of this pathway by the compounds from natural sources may provide a better targeted approach with improved therapeutic outcome. The study was carried out to test the ability of phenylpropanoic acid derivatives to inhibit the NLRP3 inflammasome pathway and IL-1ß release. The main purpose of the study was to test the active derivatives with respect to the possible molecular interactions in-silico, effect on mRNA expression of molecular markers and, effect on released cytokine. Autodock along with SwissADME was used to carry out the in-silico studies including the prediction studies as well as molecular docking studies. The effect of test compounds on mRNA expression of important proteins was evaluated against U87MG cells using RT-qPCR. The changes in released cytokine levels was evaluated using ELISA. The tested phenylpropanoic acid derivatives had a comparable molecular docking profile to that of selected standards. The prediction studies indicated that these compounds have suitable properties to be a drug candidate. mRNA expression studies showed that the derivatives can downregulate the proteins responsible for inflammasome activation and same was reflected in ELISA when the concentration of released cytokine was evaluated. Based on the above results, phenylpropanoic acid derivatives have potential to be developed as specific NLRP3-inflammasome inhibitors.

Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders.

Spermidine is a naturally occurring endogenous polyamine synthesized from diamine putrescine. It is a well-known autophagy inducer that maintains cellular and neuronal homeostasis. Healthy brain development and function are dependent on brain polyamine concentration. Polyamines interact with the opioid system, glutamatergic signaling and neuroinflammation in the neuronal and glial compartments. Among the polyamines, spermidine is found highest in the human brain. Age-linked fluctuations in the spermidine levels may possibly contribute to the impairments in neural network and neurogenesis. Exogenously administered spermidine helps in the treatment of brain diseases. Further, current studies highlight the ability of spermidine to promote longevity by inducing autophagy. Still, the causal neuroprotective mechanism of spermidine in neuronal dysfunction remains unidentified. This review aims to summarize various neuroprotective effects of spermidine related to anti-aging/ anti-inflammatory properties and the prevention of neurotoxicity that helps in achieving beneficial effects in age-related neurological disorder. We also expose the signaling cascades modulated by spermidine which might result in therapeutic action. The present review highlights clinical studies along with in-vivo and in-vitro preclinical studies to provide a new dimension for the therapeutic potential of spermidine in neurological disorders.

In vitro cytotoxicity of montelukast in HAPI and SH-SY5Y cells.

Montelukast is a cysteinyl leukotriene (CysLT) receptor antagonist with efficacy against a variety of diseases, including asthma and inflammation-related conditions. However, various neuropsychiatric events (NEs) suspected to be related to montelukast have been reported recently, with limited understanding on their association and underlying mechanisms. This study aimed to investigate whether montelukast can induce neuroinflammation and neurotoxicity in microglial HAPI cells and neural SH-SY5Y cells. The present study also compared the effects of montelukast with a 5-lipoxygenase inhibitor (zileuton) and a cyclooxygenase-2 inhibitor (celecoxib) to better understand modulation of related pathways. HAPI or SH-SY5Y cells were treated with the indicated drugs (3.125 µM-100 µM) for 24 h to investigate drug-induced neuroinflammation and neurotoxicity. Montelukast induced cytotoxicity in HAPI cells (50-100 µM), accompanied with caspase-3/7 activation, prostaglandin E2 (PGE2) release, and reactive oxygen species (ROS) production. Whilst both montelukast and zileuton down-regulated CysLT release in HAPI cells, zileuton did not significantly affect cell viability or inflammatory and oxidative factors. Celecoxib decreased HAPI cell viability (6.25-100 µM), accompanied with increasing caspase-3/7 activation and ROS production, but in contrast to montelukast increased CysLT release and decreased PGE2 production. Similar to observations in HAPI cells, both montelukast and celecoxib (50-100 µM) but not zileuton produced toxicity in SH-SY5Y neuroblastoma cells. Similarly, CM from HAPI cells treated with either montelukast or zileuton produced toxicity in SH-SY5Y cells. The results of the current study show the capability of montelukast to directly induce toxicity and inflammation in HAPI cells, possibly through the involvement of PGE2 and ROS, and toxicity in undifferentiated SH-SY5Y neuroblastoma cells. The current study highlights the importance of consideration between benefit and risk of montelukast usage and provides references for future investigation on decreasing montelukast-related NEs.

Cyclooxygenase-2 inhibitors delay relapse and reduce Prostate Specific Antigen (PSA) velocity in patients treated with radiotherapy for nonmetastatic prostate cancer: a pilot study.

INTRODUCTION: A common treatment for localized prostate cancer (PCa) is radiotherapy; however, effectiveness is hampered because of toxicities and tumor resistance. Cyclooxygenase-2 (COX-2) inhibitors have been identified as potential agents that could improve treatment outcomes and have demonstrated ability to increase the radiosensitivity of many human carcinomas. This retrospective human study aims to investigate the ability of COX-2 inhibitors, celecoxib, and meloxicam, to improve treatment outcomes after radiotherapy. METHODS: Prostate Specific Antigen (PSA) data of eligible patients were obtained from Genesis Cancer Care, Southport, Australia. The primary outcome was the percentage of patients in each group that had reached biochemical relapse at two and five years after treatment. Secondary outcomes included time to biochemical relapse and PSA velocity. RESULTS: At two and five years after treatment, both the celecoxib (6.7%, 18.3%) and meloxicam (0.0%, 18.9%) showed lower relapse rates than the control (8.6%, 31.0%). Although not statistically significant, these results are clinically significant. In addition, the two treatment groups were found to increase the time to relapse, 46.20 months for celecoxib and 54.15 months for meloxicam, compared with the control group, 35.53 months. A similar trend was shown for PSA velocity with both treatment groups demonstrating lower PSA velocities compared with control. CONCLUSIONS: This study provides further evidence to the potential for COX-2 inhibitors to address gaps in localizedz PCa treatment by demonstrating high clinical significance for the use of celecoxib and meloxicam. Further research should be conducted including larger retrospective studies and prospective studies to fully evaluate the benefits of COX-2 inhibitors in combination with radiotherapy for PCa.

An Overview on Chemotherapy-induced Cognitive Impairment and Potential Role of Antidepressants.

BACKGROUND: Cognitive impairment is an adverse reaction of cancer chemotherapy and is likely to affect up to 75% of patients during the treatment and 35% of patients experience it for several months after the chemotherapy. Patients manifest symptoms like alteration in working ability, awareness, concentration, visual-verbal memory, attention, executive functions, processing speed, fatigue and behavioural dysfunctions. Post-chemotherapy, cancer survivors have a reduced quality of life due to the symptoms of chemobrain. Apart from this, there are clinical reports which also associate mood disorders, vascular complications, and seizures in some cases. Therefore, the quality of lifestyle of cancer patients/ survivors is severely affected and only worsens due to the absence of any efficacious treatments. With the increase in survivorship, it's vital to identify effective strategies, until then only symptomatic relief for chemobrain can be provided. The depressive symptoms were causally linked to the pathophysiological imbalance between the pro and antiinflammatory cytokines. CONCLUSION: The common causative factor, cytokines can be targeted for the amelioration of an associated symptom of both depression and chemotherapy. Thus, antidepressants can have a beneficial effect on chemotherapy-induced inflammation and cognitive dysfunction via cytokine balance. Also, neurogenesis property of certain antidepressant drugs rationalises their evaluation against CICI. This review briefly glances upon chemotherapy-induced cognitive impairment (CICI), and the modulatory effect of antidepressants on CICI pathomechanisms.

Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury.

Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.

Review of the anti-inflammatory effect of SIRT1 and SIRT2 modulators on neurodegenerative diseases.

Neurodegenerative disease refers to a range of chronic and progressive disorders that are characterized by dysfunction and loss of neurons. Neurodegeneration involves protein misfolding, oxidative injury, impaired mitochondrial function, neurotrophin deficiency and may also involve neuroinflammation. The sirtuin family of proteins plays a key role in this process suggesting that modulation of sirtuin can modify disease progression. This review examines experimental and clinical evidence relating to the potential role of SIRT1 and SIRT2, and their modulators in neurodegenerative diseases. Both neuroprotective effects and negative effects of SIRT1 activators, SIRT1 inhibitors and SIRT2 activators are discussed in a range of different disease models, including in vitro and in vivo Alzheimer's disease (AD), Parkinson's disease (PD), Huntingdon's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). This highlights the potential of SIRT1 and SIRT 2 modulators as potential therapeutic agents. However, there is a paucity of clinical trials related to the effects of selective SIRT1 modulators, selective SIRT2 modulators or dual SIRT1/2 modulators on neuroinflammation and subsequent neurodegeneration.

Possible involvement of metformin in downregulation of neuroinflammation and associated behavioural changes in mice.

Metformin (MET), a biguanide oral hypoglycaemic agent, recently has been shown to be effective in various conditions other than type-2 diabetes including cancer, stroke, weight reduction, and polycystic ovarian syndrome, to name a few. MET has also possessed antioxidant and antiinflammatory properties by activation of AMPK . This study was aimed at evaluating the effects of MET on lipopolysaccharide (LPS)-induced systemic and neuroinflammation, oxidative stress, and behavioural changes. The study consisted of six groups, where three selected doses of MET (100, 200, and 300 mg/kg) were employed in male Swiss albino mice, with one group of imipramine (IMI), saline, and LPS each. Systemic inflammation was induced by injecting LPS (1.5 mg/kg) by intraperitoneal route. A battery of behavioural tests including open field, forced swim, and tail suspension tests were employed to assess the impact of systemic inflammation on exploratory behaviour and learned helplessness. LPS induced significant immobility with profound symptoms of sickness behaviour. Furthermore, LPS led to significant increase in serum and brain proinflammatory cytokines TNF-α and IL-6; and also increased lipid peroxidation with reduced glutathione levels. Pretreatment of the animals with 100 and 200 mg/kg of MET significantly reduced both systemic and central inflammatory markers along with protecting against LPS-induced oxidative stress. The higher dose, 300 mg/kg of MET was not effective against most of LPS-induced biochemical changes. Our preliminary results from this study suggest the antiinflammatory and neuroprotective effects of MET in LPS-induced model of sickness behaviour and neuroinflammation.