Jaya Kumar

Oxidative Stress in Oral Diseases: Understanding Its Relation with Other Systemic Diseases

Oxidative stress occurs in diabetes, various cancers, liver diseases, stroke, rheumatoid arthritis, chronic inflammation, and other degenerative diseases related to the nervous system. The free radicals have deleterious effect on various organs of the body. This is due to lipid peroxidation and irreversible protein modification that leads to cellular apoptosis or programmed cell death. During recent years, there is a rise in the oral diseases related to oxidative stress. Oxidative stress in oral disease is related to other systemic diseases in the body such as periodontitis, cardiovascular, pancreatic, gastric, and liver diseases. In the present review, we discuss the various pathways that mediate oxidative cellular damage. Numerous pathways mediate oxidative cellular damage and these include caspase pathway, PERK/NRF2 pathway, NADPH oxidase 4 pathways and JNK/mitogen-activated protein (MAP) kinase pathway. We also discuss the role of inflammatory markers, lipid peroxidation, and role of oxygen species linked to oxidative stress. Knowledge of different pathways, role of inflammatory markers, and importance of low-density lipoprotein, fibrinogen, creatinine, nitric oxide, nitrates, and highly sensitive C-reactive proteins may be helpful in understanding the pathogenesis and plan better treatment for oral diseases which involve oxidative stress.

The effects of acute ethanol administration on ethanol withdrawal-induced anxiety-like syndrome in rats: A biochemical study

Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW.

Alcohol addiction- metabotropic glutamate receptor subtype 5 and its ligands: How they all come together?

In the past decade, many studies have highlighted the role of metabotropic glutamate receptor subtype 5 (mGlu5) modulators in attenuating alcohol-related biological effects such as alcohol consumption, alcohol-seeking and relapse-like behaviors. Taken together, these findings suggest that pharmacological agents acting at mGlu5 could be promising tools in curbing inebriation. mGlu5s are present abundantly in brain regions known to be involved in emotion regulation, motivation and drug administration. On a cellular level, they are primarily located at the postsynaptic part of the neuron where the receptor is functionally linked to various downstream proteins that are involved in cell signaling and gene transcription that mediate the alcohol-induced neuroplasticity. As well, the discovery of a functional link between mGlu5 and a specific isozyme, Protein Kinase C epsilon (PKCε) in mediating the attenuating effects of selective negative allosteric modulators of mGlu5 such as methyl- 6(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) has sparked interesting speculations. In this article, we shall review the following: the effects of acute and chronic alcohol intake on mGlu5 signaling; the effects of mGlu5 ligands on alcohol-related neurobehavioral changes that are currently being studied both at pre-clinical and clinical stages; and the mechanisms underlying the pharmacological effects of these drugs.

Ethanol-Induced Changes in PKCε: From Cell to Behavior

The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCε is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCε expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCε expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCε to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCε, ethanol-induced changes in PKCε expression, the regulation of ethanol-induced PKCε activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCε-RACKε translocation in the presence of ethanol, and the existing literature on the role of PKCε in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build.

Sleep Related Epilepsy and Pharmacotherapy: An Insight

In the last several decades, sleep-related epilepsy has drawn considerable attention among epileptologists and neuroscientists in the interest of new paradigms of the disease etiology, pathogenesis and management. Sleep-related epilepsy is nocturnal seizures that manifest solely during the sleep state. Sleep comprises two distinct stages i.e., non-rapid eye movement (NREM) and rapid eye movement (REM) that alternate every 90 min with NREM preceding REM. Current findings indicate that the sleep-related epilepsy manifests predominantly during the synchronized stages of sleep; NREM over REM stage. Sleep related hypermotor epilepsy (SHE), benign partial epilepsy with centrotemporal spikes or benign rolandic epilepsy (BECTS), and Panayiotopoulos Syndrome (PS) are three of the most frequently implicated epilepsies occurring during the sleep state. Although some familial types are described, others are seemingly sporadic occurrences. In the present review, we aim to discuss the predominance of sleep-related epilepsy during NREM, established familial links to the pathogenesis of SHE, BECTS and PS, and highlight the present available pharmacotherapy options.

Dietary Acrylamide and the Risks of Developing Cancer: Facts to Ponder

Acrylamide (AA) is a water soluble white crystalline solid commonly used in industries. It was listed as an industrial chemical with potential carcinogenic properties. However to date, AA was used to produce polyacrylamide polymer, which was widely used as a coagulant in water treatment; additives during papermaking; grouting material for dams, tunnels, and other underground building constructions. AA in food could be formed during high-temperature cooking via several mechanisms, i.e., formation via acrylic acid which may be derived from the degradation of lipid, carbohydrates, or free amino acids; formation via the dehydration/decarboxylation of organic acids (malic acid, lactic acid, and citric acid); and direct formation from amino acids. The big debate is whether this compound is toxic to human beings or not. In the present review, we discuss the formation of AA in food products, its consumption, and possible link to the development of any cancers. We discuss the body enzymatic influence on AA and mechanism of action of AA on hormone, calcium signaling pathways, and cytoskeletal filaments. We also highlight the deleterious effects of AA on nervous system, reproductive system, immune system, and the liver. The present and future mitigation strategies are also discussed. The present review on AA may be beneficial for researchers, food industry, and also medical personnel.

Serotonin Selective Reuptake Inhibitors (SSRIs) and Female Sexual Dysfunction (FSD): Hypothesis on Its association and options of treatment.

Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter- playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potential confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies. The exact mechanism of FSD-induced SSRIs is unknown. It has been postulated that although SSRIs may modulate other neurotransmitter system such as nitric oxide (NO), noradrenergic and dopamine in inducing FSD. In the present review, we highlight current evidence regarding potential mechanism of SSRIs in causing FSD, which include low sexual desire (low libido), arousal difficulties (lack of lubrication), and anorgasmia. The specific association of FSD to SSRI use, has not been ellucidated. The relationship is dose-dependent, and may vary among the groups with respect to mechanism of serotonin and dopamine reuptake, induction of release of prolactin from the pituitary gland, anticholinergic side-effects, inhibition of NO synthesis and emotional-memory circuit encryption for sexual experiences. Various interventional strategies exist regarding the treatment of SSRI-induced FSD and this includes tolerance, titration dosage, substitution to another antidepressant drug and psychotherapy. There is a need of better understanding of SSRIs-induced FSD for better treatment outcome.

Understanding the pathophysiology of premature ejaculation: Bridging the link between pharmacological and psychological interventions

Premature ejaculation (PE) is one of the commonest male sexual dysfunctions. It is characterized by ejaculation which occurs before or soon after vaginal penetration, which causes significant psychological distress to the individual, and his partner. The exact cause of PE is still unknown but several mechanisms are proposed, and these involve complex interactions of neurophysiological, psychosocial, and cognitive factors. We discuss the role of serotonin, nitric oxide, phosphodiesterase enzymes and other neurotransmitters. Treatment of PE tends to co-occur with other sexual difficulties, especially erectile dysfunction (ED). Treatment with selective serotonin reuptake inhibitors (SSRIs) and Dapoxitene are also discussed in detail. The treatment strategy requires a comprehensive holistic approach incorporating both combination of psychopharmacological agent and cognitive-behavioral therapy (CBT). The present review highlights the integration of the hypothalamic-neural and reverberating emotional circuit and discusses the etiology and treatment for patients with PE.

Novel Pharmacotherapeutic Approaches in Treatment of Alcohol Addiction

In the past two decades, the search for novel pharmacotherapies to treat alcohol addiction has been a global endeavor. This has resulted in several drugs that have been approved and successfully marketed for public use while some are still in the testing phase. These pharmacological agents, though effective for the treatment of alcoholism, are not without shortcomings; such as abuse potential, serious mental and physical adverse effects, interaction with alcohol and also poor metabolism and excretion. As more is being understood about the neurobiology of alcohol addiction as well as the unique pharmacological action of these drugs, new agents are evaluated for potential benefits when used as an adjunct in combination therapy. This review article summarizes the novel pharmacotherapeutic approaches used in the treatment of alcohol addiction by focusing on the drugs, which include neramexane, gabapentin, baclofen, aripiprazole, nalmafene, and quetiapine.

Co-Morbid Erectile Dysfunction (Ed) and Antidepressant Treatment in a Patient – A Management Challenge?

Throughout the world, antidepressants (AD) and phosphodiesterase-5 inhibitors (PDE-5i) are the commonly prescribed psychopharmacological agents for treating patients with co-morbid mental health problem and sexual dysfunction (SD). The serotonergic and noradrenergic ADs, although effective, are not without any SD adverse-effects, especially erectile dysfunction (ED). ED is a failure to obtain a satisfactory erection for rewarding sexual coitus during the phases of males sexual arousal. It is recognized as an important reason why non-adherence to treatment was observed in patients who were on AD. AD intervention caused remission to some of the pre- treatment psychopathology of ED. However, in many patients, AD potentially magnified the unwanted sexual sideeffects. This made the situation challenging for the mental health professional. These challenges are based on the complexity of ED, its etiology and the associated risk factors, which further add to its AD side-effect. The neuro-psychopharmacological basis for AD treatment selection was deliberated. Bio-psycho-social interventions are recommended at two pivotal stages. Firstly, a step should be taken for proper assessment (e.g. detailed history, psychosocial and laboratory investigations); and identify few modifiable risk factors for ED and associated mental health issues. Secondly, with guidance of an algorithm pathway, a practical intervention should include strategies such as dose reduction, augmentation or changing to an AD with lesser or no sexual adverse-effects. It is recommended that bupropion and mirtazepine to be prescribed when patients develop adverse sexual effects with serotonin selective reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI) and tricyclic antidepressant (TCA). Few suggestions which may be borne in mind are revising sexual scripts and improving sexual techniques, life-style modifications, psychotherapy and other nonpharmacological approaches which may be beneficial to both patients and their partners.