Estimating the risk of irreversible post-SSRI sexual dysfunction (PSSD) due to serotonergic antidepressants.

BACKGROUND: Sexual dysfunction is a common side effect of Serotonergic antidepressants (SA) treatment, and persists in some patients despite drug discontinuation, a condition termed post-SSRI sexual dysfunction (PSSD). The risk for PSSD is unknown but is thought to be rare and difficult to assess. This study aims to estimate the risk of erectile dysfunction (ED) and PSSD in males treated with SAs. METHODS: A 19-year retrospective cohort analysis was conducted using a computerized database of the largest HMO in Israel. ED was defined by phosphodiesterase-5 inhibitors prescriptions. 12,302 males aged 21-49 met the following criteria: non-smokers, no medical or psychiatric comorbidities or medications associated with ED, no alcohol or substance use. Logistic regression was used for estimation of ED risk in SA-treated subjects compared to non-SA-treated controls, assessed with and without the effects of age, body mass index (BMI), socioeconomic status (SES), depression and anxiety, yielding crude and adjusted odds ratios (cOR and aOR, respectively). RESULTS: SAs were associated with an increased risk for ED (cOR = 3.6, p < 0.000001, 95% CI 2.8-4.8), which remained significant after adjusting for age, SES, BMI, depression and anxiety (aOR = 3.2, p < 0.000001, 95% CI 2.3-4.4). The risk for PSSD was 1 in 216 patients (0.46%) treated with SAs. The prevalence of PSSD was 4.3 per 100,000. CONCLUSIONS: This work offers a first assessment of the small but significant risk of irreversible ED associated with the most commonly prescribed class of antidepressants which should enhance the process of receiving adequate informed consent for therapy.

Chemosensory Ability and Sensitivity in Health and Disease: Epigenetic Regulation and COVID-19.

Throughout the animal kingdom, our two chemical senses, olfaction and gustation, are defined by two primary factors: genomic architecture of the organisms and their living environment. During the past three years of the global COVID-19 pandemic, these two sensory modalities have drawn much attention at the basic science and clinical levels because of the strong association of olfactory and gustatory dysfunction with viral infection. Loss of our sense of smell alone, or together with a loss of taste, has emerged as a reliable indicator of COVID-19 infection. Previously, similar dysfunctions have been detected in a large cohort of patients with chronic conditions. The research focus remains on understanding the persistence of olfactory and gustatory disturbances in the post-infection phase, especially in cases with long-term effect of infection (long COVID). Also, both sensory modalities show consistent age-related decline in studies aimed to understand the pathology of neurodegenerative conditions. Some studies using classical model organisms show an impact on neural structure and behavior in offspring as an outcome of parental olfactory experience. The methylation status of specific odorant receptors, activated in parents, is passed on to the offspring. Furthermore, experimental evidence indicates an inverse correlation of gustatory and olfactory abilities with obesity. Such diverse lines of evidence emerging from basic and clinical research studies indicate a complex interplay of genetic factors, evolutionary forces, and epigenetic alterations. Environmental factors that regulate gustation and olfaction could induce epigenetic modulation. However, in turn, such modulation leads to variable effects depending on genetic makeup and physiological status. Therefore, a layered regulatory hierarchy remains active and is passed on to multiple generations. In the present review, we attempt to understand the experimental evidence that indicates variable regulatory mechanisms through multilayered and cross-reacting pathways. Our analytical approach will add to enhancement of prevailing therapeutic interventions and bring to the forefront the significance of chemosensory modalities for the evaluation and maintenance of long-term health.

Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties.

BACKGROUND: Appreciable evidence suggest that dysbiosis in microbiota, reflected in gut microbial imbalance plays a key role in the pathogenesis of neuropsychiatric disorders including depression and inflammatory diseases. Recently, the antidepressant properties of ketamine have gained prominence due to its fast and long lasting effects. Additional uses for ketamine in inflammatory disorders such as irritable bowel syndrome have been suggested. However, ketamine's exact mechanism of action and potential effects on microbiome is not known. Here, we examined the effects of low dose ketamine, known to induce antidepressant effects, on stool microbiome profile in adult male Wistar rats. Animals (5/group) were injected intraperitoneally with ketamine (2.5 mg/kg) or saline, daily for 7 days and sacrificed on day 8 when intestinal stools were collected and stored at - 80 °C. DNA was extracted from the samples and the 16 S rRNA gene-based microbiota analysis was performed using 16S Metagenomics application. RESULTS: At genus-level, ketamine strikingly amplified Lactobacillus, Turicibacter and Sarcina by 3.3, 26 and 42 fold, respectively. Conversely, opportunistic pathogens Mucispirillum and Ruminococcus were reduced by approximately 2.6 and 26 fold, respectively, in ketamine group. Low levels of Lactobacillus and Turicibacter are associated with various disorders including depression and administration of certain species of Lactobacillus ameliorates depressive-like behavior in animal models. Hence, some of the antidepressant effects of ketamine might be mediated through its interaction with these gut bacteria. Additionally, high level of Ruminococcus is positively associated with the severity of irritable bowel syndrome (IBS), and some species of Mucispirillum have been associated with intestinal inflammation. Indirect evidence of anti-inflammatory role of Sarcina has been documented. Hence, some of the anti-inflammatory effects of ketamine and its usefulness in specific inflammatory diseases including IBS may be mediated through its interaction with these latter bacteria. CONCLUSION: Our data suggest that at least some of the antidepressant and anti-inflammatory effects of daily ketamine treatment for 7 days may be mediated via its interaction with specific gut bacteria. These findings further validate the usefulness of microbiome as a target for therapeutic intervention and call for more detailed investigation of microbiome interaction with central mediators of mood and/or inflammatory disorders.

Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship.

Emerging evidence suggests that sexual dysfunction emerging during treatment with selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some patients beyond drug discontinuation (post-SSRI sexual dysfunction [PSSD]). We sought to identify and characterize a series of such cases and explore possible explanatory factors and exposure-response relationship. Subjects who responded to an invitation in a forum dedicated to PSSD filled out a survey via online software. Case probability was defined according to the following 3 categories of increasing presumed likelihood of PSSD. Noncases did not meet the criteria for possible cases. Possible cases were subjects with normal pretreatment sexual function who first experienced sexual disturbances while using a single SSRI/SNRI, which did not resolve upon drug discontinuation for 1 month or longer as indicated by Arizona Sexual Experience Scale scores. High-probability cases were also younger than 50-year-olds; did not have confounding medical conditions, medications, or drug use; and had normal scores on the Hospital Anxiety and Depression Scale. Five hundred thirty-two (532) subjects completed the survey, among which 183 possible cases were identified, including 23 high-probability cases. Female sex, genital anesthesia, and depression predicted current sexual dysfunction severity, but dose/defined daily dose ratio and anxiety did not. Genital anesthesia did not correlate with depression or anxiety, but pleasureless orgasm was an independent predictor of both depression and case probability. Limitations of the study include retrospective design and selection and report biases that do not allow generalization or estimation of incidence. However, our findings add to previous reports and support the existence of PSSD, which may not be fully explained by alternative nonpharmacological factors related to sexual dysfunction, including depression and anxiety.

Roles of Epigenetics and Glial Cells in Drug-Induced Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by severe deficits in social communication and interaction, repetitive movements, abnormal focusing on objects, or activity that can significantly affect the quality of life of the afflicted. Neuronal and glial cells have been implicated. It has a genetic component but can also be triggered by environmental factors or drugs. For example, prenatal exposure to valproic acid or acetaminophen, or ingestion of propionic acid, can increase the risk of ASD. Recently, epigenetic influences on ASD have come to the forefront of investigations on the etiology, prevention, and treatment of this disorder. Epigenetics refers to DNA modifications that alter gene expression without making any changes to the DNA sequence. Although an increasing number of pharmaceuticals and environmental chemicals are being implicated in the etiology of ASD, here, we specifically focus on the molecular influences of the abovementioned chemicals on epigenetic alterations in neuronal and glial cells and their potential connection to ASD. We conclude that a better understanding of these phenomena can lead to more effective interventions in ASD.

Hypotheses on the evolution of hyaluronan: a highly ironic acid.

Hyaluronan is a high-molecular-weight glycosaminoglycan (GAG) prominent in the extracellular matrix. Emerging relatively late in evolution, it may have evolved to evade immune recognition. Chondroitin is a more ancient GAG and a possible hyaluronan precursor. Epimerization of a 4-hydroxyl in N-acetylgalactosamine in chondroitin to N-acetylglucosamine of hyaluronan is the only structural difference other than chain length between these two polymers. The axial 4-hydroxyl group extends out perpendicular from the equatorial plane of N-acetylgalactosamine in chondroitin. We suspect that this hydroxyl is a prime target for immune recognition. Conversion of a thumbs-up hydroxyl group into a thumbs-down position in the plane of the sugar endows hyaluronan with the ability to avoid immune recognition. Chitin is another potential precursor to hyaluronan. But regardless whether of chondroitin or of chitin origin, an ancient chondroitinase enzyme sequence seems to have been commandeered to catalyze the cleavage of the new hyaluronan substrate. The evolution of six hyaluronidase-like sequences in the human genome from a single chondroitinase as found in Caenorhabditis elegans can now be traced. Confirming our previous predictions, two duplication events occurred, with three hyaluronidase-like sequences occurring in the genome of Ciona intestinalis (sea squirt), the earliest known chordate. This was probably followed by en masse duplication, with six such genes present in the genome of zebra fish onwards. These events occurred, however, much earlier than predicted. It is also apparent on an evolutionary time scale that in several species, this gene family is continuing to evolve.

Epigenetic Changes Induced by High Glucose in Human Pancreatic Beta Cells.

Epigenetic changes in pancreatic beta cells caused by sustained high blood glucose levels, as seen in prediabetic conditions, may contribute to the etiology of diabetes. To delineate a direct cause and effect relationship between high glucose and epigenetic changes, we cultured human pancreatic beta cells derived from induced pluripotent stem cells and treated them with either high or low glucose, for 14 days. We then used the Arraystar 4x180K HG19 RefSeq Promoter Array to perform whole-genome DNA methylation analysis. A total of 478 gene promoters, out of a total of 23,148 present on the array (2.06%), showed substantial differences in methylation (p < 0.01). Out of these, 285 were hypomethylated, and 193 were hypermethylated in experimental vs. control. Ingenuity Pathway Analysis revealed that the main pathways and networks that were differentially methylated include those involved in many systems, including those related to development, cellular growth, and proliferation. Genes implicated in the etiology of diabetes, including networks involving glucose metabolism, insulin secretion and regulation, and cell cycle regulation, were notably altered. Influence of upstream regulators such as MRTFA, AREG, and NOTCH3 was predicted based on the altered methylation of their downstream targets. The study validated that high glucose levels can directly cause many epigenetic changes in pancreatic beta cells, suggesting that this indeed may be a mechanism involved in the etiology of diabetes.

Dihydromyricetin Protects Against Salsolinol-Induced Toxicity in Dopaminergic Cell Line: Implication for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with loss of dopaminergic neurons in the substantia nigra pars compacta. Although aging is the primary cause, environmental and genetic factors have also been implicated in its etiology. In fact, the sporadic nature of PD (i.e., unknown etiology) renders the uncovering of the exact pathogenic mechanism(s) or development of effective pharmacotherapies challenging. In search of novel neuroprotectants, we showed that butyrate (BUT), a short-chain fatty acid, protects against salsolinol (SALS)-induced toxicity in human neuroblastoma-derived SH-SY5Y cells, which are considered an in-vitro model of PD. Dihydromyricetin (DHM), a flavonoid derived from Asian medicinal plant, has also shown effectiveness against oxidative damage and neuroinflammation, hallmarks of neurodegenerative diseases. Here we show that pretreatment of SH-SY5Y cells with DHM concentration-dependently prevented SALS-induced toxicity and that a combination of DHM and BUT resulted in a synergistic protection. The effects of both DHM and BUT in turn could be completely blocked by flumazenil (FLU), a GABAA antagonist acting at benzodiazepine receptor site, and by bicuculline (BIC), a GABAA antagonist acting at orthosteric site. Beta-hydroxybutyrate (BHB), a free fatty acid 3 (FA3) receptor antagonist, also fully blocked the protective effect of DHM. BHB was shown previously to only partially block the protective effect of BUT. Thus, there are some overlaps and some distinct differences in protective mechanisms of DHM and BUT against SALS-induced toxicity. It is suggested that a combination of DHM and BUT may have therapeutic potential in PD. However, further in-vivo verifications are necessary.

Dihydromyricetin Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line: Role of GABAA Receptor.

Toxicity induced by binge alcohol drinking, particularly in adolescent and young adults, is of major medical and social consequence. Recently, we reported that butyrate, a short chain fatty acid, can protect against ethanol (ETOH)-induced toxicity in an in vitro model. In this study, we sought to evaluate the potential effectiveness of dihydromyricetin (DHM), a natural bioactive flavonoid, alone or in combination with butyrate in the same model. Exposure of SH-SY5Y cells for 24 h to 500 mM ETOH resulted in approximately 40% reduction in cell viability, which was completely prevented by 0.1 µM DHM. Combinations of DHM and butyrate provided synergistic protection against alcohol toxicity. Whereas butyrate effect was shown to be mediated primarily through fatty acid receptor 3 activation, DHM protection appears to be mediated primarily via benzodiazepine receptor site of GABAA receptor. This is based on the finding that DHM's effect could be completely prevented by pretreatment with flumazenil, a selective antagonist at this site, but not by bicuculline, a selective antagonist at the actual GABAA receptor binding site. These findings suggest potential utility of DHM alone or in combination with butyrate against ETOH-induced toxicity.

Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin.

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin. OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD). METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts. RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor. CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

Defective DSB repair correlates with abnormal nuclear morphology and is improved with FTI treatment in Hutchinson-Gilford progeria syndrome fibroblasts.

Impaired DSB repair has been implicated as a molecular mechanism contributing to the accelerating aging phenotype in Hutchinson-Gilford progeria syndrome (HGPS), but neither the extent nor the cause of the repair deficiency has been fully elucidated. Here we perform a quantitative analysis of the steady-state number of DSBs and the repair kinetics of ionizing radiation (IR)-induced DSBs in HGPS cells. We report an elevated steady-state number of DSBs and impaired repair of IR-induced DSBs, both of which correlated strongly with abnormal nuclear morphology. We recreated the HGPS cellular phenotype in human coronary artery endothelial cells for the first time by lentiviral transduction of GFP-progerin, which also resulted in impaired repair of IR-induced DSBs, and which correlated with abnormal nuclear morphology. Farnesyl transferase inhibitor (FTI) treatment improved the repair of IR-induced DSBs, but only in HGPS cells whose nuclear morphology was also normalized. Interestingly, FTI treatment did not result in a statistically significant reduction in the higher steady-state number of DSBs. We also report a delay in localization of phospho-NBS1 and MRE11, MRN complex repair factors necessary for homologous recombination (HR) repair, to DSBs in HGPS cells. Our results demonstrate a correlation between nuclear structural abnormalities and the DSB repair defect, suggesting a mechanistic link that may involve delayed repair factor localization to DNA damage. Further, our results show that similar to other HGPS phenotypes, FTI treatment has a beneficial effect on DSB repair.

Sodium Butyrate Protects Against Ethanol-Induced Toxicity in SH-SY5Y Cell Line.

Alcohol use disorder (AUD), brought about by excessive alcohol use, is associated with damages to several organs including the brain. Chronic excessive use of alcohol can compromise intestinal integrity, leading to changes in gut microbiota (GM) composition known as dysbiosis. Dysbiosis, by disruption of the gut-brain axis (GBA), further exacerbates the deleterious effects of alcohol. One of the fermentation by-products of GM is butyrate (BUT), a short-chain fatty acid (SCFA) that plays an important role in maintaining homeostasis of the GBA. Alcohol metabolism results in formation of acetaldehyde, a highly reactive compound that reacts with dopamine in the brain to form toxic adducts such as salsolinol. Recent studies indicate potential neuro-protective effects of BUT against various toxicants including salsolinol. Here, we sought to investigate whether BUT can also protect against alcohol toxicity. Pretreatment of neuroblastoma-derived SH-SY5Y cells with 500 mM ethanol (ETOH) for 24 h resulted in approximately 40% reduction in cell viability, which was totally blocked by 10 µM of either BUT or AR 420,626 (AR), a selective fatty acid 3 receptor (FA3R) agonist. The neuro-protective effects of both BUT and AR were significantly (80%) attenuated by beta-hydroxy butyrate (BHB), a selective FA3R antagonist. Interestingly, combination of BUT and AR resulted in synergistic protection against ETOH, which was totally blocked by BHB. These findings suggest potential utility of butyrate and/or FA3R agonists against ETOH-induced toxicity.

A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis.

Hyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lysosomal storage disorder, mucopolysaccharidosis (MPS) IX. We have characterized a mouse model of MPS IX and compared its phenotype with the human disease. The targeted Hyal1 allele in this model had a neomycin resistance cassette in exon 2 that replaced 753 bp of the coding region containing the predicted enzyme active site. As a result, Hyal1(-/-) animals had no detectable wild-type Hyal1 transcript, protein or serum activity. Hyal1 null animals were viable, fertile and showed no gross abnormalities at 1 year and 8 months of age. Histological studies of the knee joint showed a loss of proteoglycans occurring as early as 3 months that progressed with age. An increased number of chondrocytes displaying intense pericellular and/or cytoplasmic HA staining were detected in the epiphyseal and articular cartilage of null mice, demonstrating an accumulation of HA. Elevations of HA were not detected in the serum or non-skeletal tissues, indicating that osteoarthritis is the key disease feature in a Hyal1 deficiency. Hyal3 expression was elevated in Hyal1 null mice, suggesting that Hyal3 may compensate in HA degradation in non-skeletal tissues. Overall, the murine MPS IX model displays the key features of the human disease.

Butyrate Protects Against Salsolinol-Induced Toxicity in SH-SY5Y Cells: Implication for Parkinson's Disease.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is associated with the destruction of dopamine neurons in the substantia nigra (SN) and the formation of Lewy bodies in basal ganglia. Risk factors for PD include aging, as well as environmental and genetic factors. Recent converging reports suggest a role for the gut microbiome and epigenetic factors in the onset and/or progression of PD. Of particular relevance and potential therapeutic targets in this regard are histone deacetylases (HDACs), enzymes that are involved in chromatin remodeling. Butyrate, a short-chain fatty acid (FA) produced in the gut and presumably acting via several G protein-coupled receptors (GPCRs) including FA3 receptors (FA3Rs), is a well-known HDAC inhibitor that plays an important role in maintaining homeostasis of the gut-brain axis. Recently, its significance in regulation of some critical brain functions and usefulness in neurodegenerative diseases such as PD has been suggested. In this study we sought to determine whether butyrate may have protective effects against salsolionl (SALS)-induced toxicity in SH-SY5Y cells. SALS, an endogenous product of aldehyde and dopamine condensation, may be selectively toxic to dopaminergic neurons. SH-SY5Y cells, derived from human neuroblastoma cells, are used as a model of these neurons. Exposure of SH-SY5Y cells for 24 h to 400 µM SALS resulted in approximately 60% cell death, which was concentration-dependently prevented by butyrate. The effects of butyrate in turn were significantly attenuated by beta-hydroxy butyrate (BHB), a selective FA3R antagonist. Moreover, a selective FA3R agonist (AR 420626) also provided protective effects against SALS, which was totally blocked by BHB. These findings provide further support that butyrate or an agonist of FA3R may be of therapeutic potential in PD.

Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson's disease.

Manganese (Mn) and iron (Fe) are trace elements that are essential for proper growth and physiological functions as both play critical role in a variety of enzymatic reactions. At high concentrations, however, they can be toxic and cause neurodegenerative disorders, particularly Parkinson-like syndromes. Nicotine, on the other hand, has been shown to have neuroprotective effects against various endogenous or exogenous toxins that selectively damage the dopaminergic cells. These cells include neuroblastoma-derived SH-SY5Y cells which express significant dopaminergic activity. However, practically no information on possible neuroprotective effects of nicotine against toxicity induced by trace elements is available. Therefore, in this study we investigated the effects of nicotine on toxicity induced by manganese or iron in these cells. Exposure of SH-SY5Y cells for 24 h to manganese (20 µM) or iron (20 µM) resulted in approximately 30% and 35% toxicity, respectively. Pretreatment with nicotine (1 µM) completely blocked the toxicities of Mn and Fe. The effects of nicotine, in turn, were blocked by selective nicotinic receptor antagonists. Thus, dihydro-beta erythroidine (DHBE), a selective alpha 4-beta 2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist, as well as mecamylamine, a non-selective nicotinic antagonist all dose-dependently blocked the protective effects of nicotine against both Mn and Fe. These findings provide further support for the potential utility of nicotine or nicotinic agonists in Parkinson's disease-like neurodegenerative disorders, including those that might be precipitated by trace elements, such as Fe and Mn. Moreover, both alpha4-beta2 and alpha7 nicotinic receptor subtypes appear to mediate the neuroprotective effects of nicotine against toxicity induced by these two trace metals.

Novel targets for parkinsonism-depression comorbidity.

With the aging population growing and the incidence of neurodegenerative diseases on the rise, the researchers in the field are yet more urgently challenged to slow and/or reverse the devastating consequences of such progression. The challenge is further enforced by psychiatric co-morbid conditions, particularly the feeling of despair in these population. Fortunately, as our understanding of the neurobiological substrates of maladies affecting the central nervous system increases, more therapeutic options are also presented. In this short review while providing evidence of shared biological substrates between Parkinson's disease and depression, novel therapeutic targets and drugs are suggested. The emphasis will be on neuroplasticity underscored by roles of neurotrophic and inflammatory factors. Examples of few therapeutic drugs as well as future directions are also touched upon.

Antidepressant effects of C-Terminal domain of the heavy chain of tetanus toxin in a rat model of depression.

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) may be of therapeutic potential in motor impairments associated with Parkinson disease (PD). Since depression is a common co-morbid condition with PD, we undertook this study to determine whether Hc-TeTx might also show antidepressant-like properties and whether central brain-derived neurotrophic factor (BDNF) and/or tumor necrosis factor (TNF)-alpha are also affected by it. Adult male Wistar-Kyoto rats, a putative animal model of depression, were treated with various doses of Hc-TeTx (0, 20, 40 and 60 µg/kg, IM) and their performance in the open field locomotor activity (OFLA) as well as in the forced swim test (FST) was evaluated at 24 h, one week and two weeks after the single injection. A separate group of rats were injected with 60 µg/kg Hc-TeTx and sacrificed 24 h later for neurochemical evaluations. Hc-TeTx resulted in a dose-dependent decrease in immobility score after 24 h, whereas OFLA was not affected. Concomitant with the 24 h behavioral effects, the levels of hippocampal and frontal cortical BDNF were significantly increased, whereas the levels of TNF-alpha in both these areas were significantly decreased. The decrease in immobility scores following higher doses of Hc-TeTx were still evident after one week, but not 2 weeks of rest. These results indicate long lasting antidepressant effects of a single Hc-TeTx dose and suggest potential utility of Hc-TeTx in PD-depression co-morbidity.

Epigenetic Effects of Drugs of Abuse.

Drug addiction affects a large extent of young people and disadvantaged populations. Drugs of abuse impede brain circuits or affect the functionality of brain circuits and interfere with bodily functions. Cannabinoids (Δ9-tetrahydrocannabinol) form key constituents of marijuana derived from the cannabis plant. Marijuana is a frequently used illegal drug in the USA. Here, we review the effects of cannabinoids at the epigenetic level and the potential role of these epigenetic effects in health and disease. Epigenetics is the study of alterations in gene expression that are transmitted across generations and take place without an alteration in DNA sequence, but are due to modulation of chromatin associated factors by environmental effects. Epigenetics is now known to offer an extra mechanism of control over transcription and how genes are expressed. Insights from research at the genetic and epigenetic level potentially provide venues that allow the translation of the biology of abused drugs to new means of how to treat marijuana substance use disorder or other addictions using pharmacotherapeutic tools.

Protective Effects of Donepezil Against Alcohol-Induced Toxicity in Cell Culture: Role of Caspase-3.

Ethanol (EtOH) is one of the most frequently abused drugs with heavy health, economic, and societal burdens. Although moderate to low EtOH may have some neuroprotective effects, heavy EtOH consumption associated with high blood alcohol level (BAL) can be quite detrimental. The brain is particularly vulnerable to the damaging effects of high BAL, leading to neuronal loss, cognitive, and behavioral deficits. Although the exact causes of these detriments are not fully elucidated, it is believed that damage to the cholinergic system is at least partially responsible for the cognitive impairment. Thus, high BAL may result in selective apoptotic damage to the cholinergic neurons. Donepezil (DON), a centrally acting, reversible and non-competitive acetylcholinesterase (AChE) inhibitor, approved for use in Alzheimer's disease (AD), may also attenuate EtOH-induced cognitive impairment. Cognitive effects of DON might be due to an anti-apoptotic activity as some AChE inhibitors have been shown to have this property. The aim of this study was to determine whether DON might protect against EtOH-induced toxicity and whether such protection might be apoptotically mediated. We exposed the human neuroblastoma-derived, SH-SY5Y cells to a relatively high concentration of EtOH (500 mM) for 24 h and evaluated the effects of two concentrations of DON (0.1 and 1.0 µM) on alcohol-induced toxicity and caspase-3, an apoptotic marker. We found a dose-dependent protection of DON against EtOH-induced toxicity as well as dose-dependent attenuation of EtOH-induced increases in caspase-3 levels. Thus, DON may inhibit apoptosis as well as alcohol-induced toxicity.

The Effect of Citalopram on Genome-Wide DNA Methylation of Human Cells.

Commonly used pharmaceutical drugs might alter the epigenetic state of cells, leading to varying degrees of long-term repercussions to human health. To test this hypothesis, we cultured HEK-293 cells in the presence of 50 µM citalopram, a common antidepressant, for 30 days and performed whole-genome DNA methylation analysis using the NimbleGen Human DNA Methylation 3x720K Promoter Plus CpG Island Array. A total of 626 gene promoters, out of a total of 25,437 queried genes on the array (2.46%), showed significant differential methylation (p < 0.01); among these, 272 were hypomethylated and 354 were hypermethylated in treated versus control. Using Ingenuity Pathway Analysis, we found that the chief gene networks and signaling pathways that are differentially regulated include those involved in nervous system development and function and cellular growth and proliferation. Genes implicated in depression, as well as genetic networks involving nucleic acid metabolism, small molecule biochemistry, and cell cycle regulation were significantly modified. Involvement of upstream regulators such as BDNF, FSH, and NFκB was predicted based on differential methylation of their downstream targets. The study validates our hypothesis that pharmaceutical drugs can have off-target epigenetic effects and reveals affected networks and pathways. We view this study as a first step towards understanding the long-term epigenetic consequences of prescription drugs on human health.