Current Neuropharmacology - Volume 20, Issue 10, 2022

COVID 19 pandemic and mass vaccination campaigns have revealed the situation of the most vulnerable patients. In this work, we focused our attention to patients who have Multiple Sclerosis (MS), particularly in treatment with cladribine tablets, trying to understand if and when it is possible to administer the vaccine successfully. In light of the novel topic, we studied the existing literature and analysed experiences with previous vaccinations, such as influenza and VZV, as well as data from countries where vaccination campaigns had already begun. Overall, we have taken into account the mechanism of action, the pharmacokinetic/pharmacodynamic of cladribine, and the changes in the immune system after its administration, together with the preliminary data about the humoral response to influenza, VZV, and SARS-CoV-2 vaccinations in cladribine treated patients. In conclusion, data showed that the use of cladribine tablets seems to permit flexibility regarding vaccination timing and we suggest that vaccination in those patients should be safe and effective. The current COVID 19 pandemic has re-ignited the interest in vaccines and vaccination procedures. The importance of including fragile individuals has increased as a result of mass vaccination. Millions of patients with multiple sclerosis (MS) around the world are debating whether they can safely receive their vaccine shot with the same efficacy despite receiving immune-modulating or immune-suppressive treatments. In the absence of conclusive empirical data, we will review and discuss the available evidence and the reasonable conclusions for one specific treatment, namely cladribine tablets (Mavenclad).

Background: While Alzheimer’s dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin for cognition have been divergent across trials. Objective: The current network meta-analysis (NMA) was conducted under the frequentist model to evaluate the potential beneficial effects of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison to other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric). Methods: The primary outcome was the changes in the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer’s dementia. The secondary outcomes were changes in the quality of life, behavioral disturbance, and acceptability (i.e., drop-out due to any reason and rate of any adverse event reported). Results: The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed the medium-term lowdose melatonin to be associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo. Conclusion: The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

Autism spectrum disorder (ASD) is a neurological condition that directly affects brain functions and can culminate in delayed intellectual development, problems in verbal communication, difficulties in social interaction, and stereotyped behaviors. Its etiology reveals a genetic basis that can be strongly influenced by socio-environmental factors. Ion channels controlled by ligand voltage-activated calcium, sodium, and potassium channels may play important roles in modulating sensory and cognitive responses, and their dysfunctions may be closely associated with neurodevelopmental disorders such as ASD. This is due to ionic flow, which is of paramount importance to maintaining physiological conditions in the central nervous system and triggers action potentials, gene expression, and cell signaling. However, since ASD is a multifactorial disease, treatment is directed only to secondary symptoms. Therefore, this research aims to gather evidence concerning the principal pathophysiological mechanisms involving ion channels in order to recognize their importance as therapeutic targets for the treatment of central and secondary ASD symptoms.

Lithium is a well-known FDA-approved treatment for bipolar and mood disorders. Lithium has been an enigmatic drug with multifaceted actions involving various neurotransmitters and intricate cell signalling cascades. Recent studies highlight the neuroprotective and neurotrophic actions of lithium in amyotrophic lateral sclerosis, Alzheimer’s disease, intracerebral hemorrhage, and epilepsy. Of note, lithium holds a significant interest in epilepsy, where the past reports expose its non-specific proconvulsant action, followed lately by numerous studies for anti-convulsant action. However, the exact mechanism of action of lithium for any of its effects is still largely unknown. The present review integrates findings from several reports and provides detailed possible mechanisms of how a single molecule exhibits marked pro-epileptogenic as well as anti-convulsant action. This review also provides clarity regarding the safety of lithium therapy in epileptic patients.

The cerebellum is a well-established primary brain center in charge of controlling sensorimotor functions and non-motor functions. Recent reports depicted the significance of cerebellum in higher-order cognitive functions, including emotion-processing, language, reward-related behavior, working memory, and social behavior. As it can influence diverse behavioral patterns, any defects in cerebellar functions could invoke neuropsychiatric diseases as indicated by the incidence of alexithymia and induce alterations in emotional and behavioral patterns. Furthermore, its defects can trigger motor diseases, such as ataxia and Parkinson’s disease (PD). In this review, we have extensively discussed the role of cerebellum in motor and non-motor functions and how the cerebellum malfunctions in relation to the neural circuit wiring as it could impact brain function and behavioral outcomes in patients with neuropsychiatric diseases. Relevant data regarding cerebellar non-motor functions have been vividly described, along with anatomy and physiology of these functions. In addition to the defects in basal ganglia, the lack of activity in motor related regions of the cerebellum could be associated with the severity of motor symptoms. All together, this review delineates the importance of cerebellar involvement in patients with PD and unravels a crucial link for various clinical aspects of PD with specific cerebellar sub-regions.

Background: Stroke, especially ischemic stroke, is a leading disease associated with death and long-term disability with limited therapeutic options. Neuronal death caused by vascular impairment, programmed cell death and neuroinflammation has been proven to be associated with increased stroke severity and poor stroke recovery. In light of this, a development of neuroprotective drugs targeting injured neurons is urgently needed for stroke treatment. Netrin-1, known as a bifunctional molecule, was originally described to mediate the repulsion or attraction of axonal growth by interacting with its different receptors. Importantly, accumulating evidence has shown that netrin-1 can manifest its beneficial functions to brain tissue repair and neural regeneration in different neurological disease models. Objective: In this review, we focus on the implications of netrin-1 and its possibly involved pathways on neuroprotection after ischemic stroke, through which a better understanding of the underlying mechanisms of netrin-1 may pave the way to novel treatments. Methods: Peer-reviewed literature was recruited by searching databases of PubMed, Scopus, Embase, and Web of Science till the year 2021. Conclusion: There has been certain evidence to support the neuroprotective function of netrin-1 by regulating angiogenesis, autophagy, apoptosis and neuroinflammation after stroke. Netrin-1 may be a promising drug candidate in reducing stroke severity and improving outcomes.

Viruses have been classified as non-living because they require a cellular host to support their replicative processes. Empirical investigations have significantly advanced our understanding of the many strategies employed by viruses to usurp and divert host regulatory and metabolic processes to drive the synthesis and release of infectious particles. The recent emergence of SARS-CoV-2 has permitted us to evaluate and discuss a potentially novel classification of viruses as living entities. The ability of SARS CoV-2 to engender comprehensive regulatory control of integrative cellular processes is strongly suggestive of an inherently dynamic informational registry that is programmatically encoded by linear ssRNA sequences responding to distinct evolutionary constraints. Responses to positive evolutionary constraints have resulted in a single-stranded RNA viral genome that occupies a threedimensional space defined by conserved base-paring resulting from a complex pattern of both secondary and tertiary structures. Additionally, regulatory control of virus-mediated infectious processes relies on extensive protein-protein interactions that drive conformational matching and shape recognition events to provide a functional link between complementary viral and host nucleic acid and protein domains. We also recognize that the seamless integration of complex replicative processes is highly dependent on the precise temporal matching of complementary nucleotide sequences and their corresponding structural and non-structural viral proteins. Interestingly, the deployment of concerted transcriptional and translational activities within targeted cellular domains may be modeled by artificial intelligence (AI) strategies that are inherently fluid, self-correcting, and adaptive at accommodating temporal changes in host defense mechanisms. An in-depth understanding of multiple self-correcting AIassociated viral processes will most certainly lead to novel therapeutic development platforms, notably the design of efficacious neuropharmacological agents to treat chronic CNS syndromes associated with long-COVID. In summary, it appears that viruses, notably SARS-CoV-2, are very much alive due to acquired genetic advantages that are intimately entrained to existential host processes via evolutionarily constrained AI-associated learning paradigms.

The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer’s disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer’s disease. The traditional “gain of toxic function” properties assigned to amyloid proteins are, however, contrasted by several reports highlighting neuroprotective effects of amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address the paradoxical nature of this hormone's signaling in the context of AD pathogenesis.

In view of the significant role of H2S in brain functioning, it is proposed that H2S may also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of the present review is to discuss the neuroprotective effects of H2S against toxicity of a wide spectrum of endogenous and exogenous agents involved in the pathogenesis of neurological diseases as etiological factors or key players in disease pathogenesis. Generally, the existing data demonstrate that H2S possesses neuroprotective effects upon exposure to endogenous (amyloid β, glucose, and advanced-glycation end-products, homocysteine, lipopolysaccharide, and ammonia) and exogenous (alcohol, formaldehyde, acrylonitrile, metals, 6-hydroxydopamine, as well as 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl pyridine ion (MPP)) neurotoxicants. On the one hand, neuroprotective effects are mediated by S-sulfhydration of key regulators of antioxidant (Sirt1, Nrf2) and inflammatory response (NF-ΚB), resulting in the modulation of the downstream signaling, such as SIRT1/TORC1/CREB/BDNF-TrkB, Nrf2/ARE/HO-1, or other pathways. On the other hand, H2S appears to possess a direct detoxicative effect by binding endogenous (ROS, AGEs, Aβ) and exogenous (MeHg) neurotoxicants, thus reducing their toxicity. Moreover, the alteration of H2S metabolism through the inhibition of H2S-synthetizing enzymes in the brain (CBS, 3-MST) may be considered a significant mechanism of neurotoxicity. Taken together, the existing data indicate that the modulation of cerebral H2S metabolism may be used as a neuroprotective strategy to counteract neurotoxicity of a wide spectrum of endogenous and exogenous neurotoxicants associated with neurodegeneration (Alzheimer’s and Parkinson’s disease), fetal alcohol syndrome, hepatic encephalopathy, environmental neurotoxicant exposure, etc. In this particular case, modulation of H2S-synthetizing enzymes or the use of H2S-releasing drugs should be considered as the potential tools, although the particular efficiency and safety of such interventions are to be addressed in further studies.

Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant, and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro-convulsant effects of fruits used in relation to seizures in hopes of providing a good therapeutic reference to epileptic patients and their carers. Three databases, SCOPUS, ScienceDirect, and PubMed, were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit due to its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.

Although few clinical trials examined the efficacy of bupropion to treat sexual dysfunction among female patients, a comprehensive and objective synthesis of the best available evidence is still lacking. To date, to the best of our knowledge, there are no published systematic reviews or meta-analyses specifically focusing on the role of bupropion in the treatment of female sexual dysfunction. The main objective of the present study was to evaluate the efficacy of bupropion in the treatment of female sexual dysfunction, and we hypothesized that bupropion is efficient in treating female patients with sexual dysfunction. This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search for published literature was performed using Ovid, Medline, Scopus, Cochrane Library, Science Direct, and PubMed databases. In our study, we found that bupropion was almost three-fold more favorable in improving problems with sexual desire (pool estimate 2.845, 95% CI: 0.215 to 5.475, I2= 95.6%, p=0.034). A meta-regression was performed to explore heterogeneity and we found that only the dosage of bupropion was statistically significant in explaining the variance, i.e., the lower the dosage (150 mg vs. 300 mg), the better the improvement in the sexual desire of women with hypoactive sexual desire disorder (HSDD). Based on the results of this systematic review and metaanalysis, there is a potential role of bupropion as an effective treatment for women with HSDD.

Background: Although a previous review illustrated the efficacy of melatonin receptor agonists (MRAs) in preventing delirium, some recent randomized controlled trials (RCTs) did not confirm these effects. Objectives: This study systematically reviewed the efficacy, acceptability, and tolerability of MRAs for delirium prevention. Materials and Methods: We searched electronic databases, including Scopus, PubMed, CINAHL, and Controlled Trials Register, from their inception to February 20, 2022. The primary efficacy outcome was delirium incidence rate after MRA administration; relative risks (RRs), overall discontinuation, and discontinuation due to adverse events are also presented. Results: The overall pooled incidence rates of delirium in MRA-treated and placebo-treated groups were significantly different with RR (95% CI)=0.66(0.52, 0.84, ), I2=59%. Similarly, the incidence rate was significantly lower in the melatonin-treated group than in the placebo-treated group [RR (95% CI) =0.65 (0.49, 0.88), I2=65%]. Unfortunately, incidence rates were not significantly different between ramelteon-treated and placebo-treated groups [RR (95% CI) =0.67 (0.42, 1.08), I2=50%]. The pooled incidence rate of delirium in either melatonin or ramelteon-treated groups was not significantly different from the placebo-treated group in elderly patients. The pooled incidence rate of delirium was significantly lower in the melatonin-treated group than in the benzodiazepinetreated group. Conclusion: Based on this review, melatonin could prevent delirium with a small effect size. However, ramelteon did not show efficacy in preventing delirium. Additionally, neither melatonin nor ramelteon individually showed effectiveness in preventing delirium in elderly patients. Therefore, using MRAs to prevent delirium in clinical practice should be cautious. However, future welldefined and large sample size studies could verify these findings.

Background: Antipsychotics are known to be associated with metabolic syndromes (MetS). Chlorpromazine (CPZ) and Clozapine (CLZ) are currently the most commonly used antipsychotics in low-income districts of China. However, potential differences in the long-term effects of CPZ and CLZ on MetS in schizophrenia inpatients are not well understood. Here, we aimed to identify any MetS profile differences between long-term schizophrenia patients who were prescribed either CPZ or CLZ at a primary psychiatric hospital. Methods: We recruited a total of 204 male schizophrenia patients who received either CPZ or CLZ. We measured their weight, height, body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), and systolic blood pressure (SBP), as well as their biochemical indicators, including fasting blood glucose (FBS), triglycerides (TG), cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c). Results: The MetS prevalence in the CPZ and CLZ groups was 31% and 37.5%, respectively. The CLZ group had significantly higher DBP levels and a higher incidence of dyslipidemia (HDL-c) but lower HDL-c and TC levels than the CPZ group. We also determined that smoking history, BMI, and duration of hospitalisation were risk factors for the development of MetS. Moreover, we found that CPZ and CLZ were correlated with the same risk for developing MetS and that BMI was a vital risk factor of MetS for both the CPZ and CLZ groups. Conclusion: Long-term CPZ and CLZ prescriptions were associated with similar profiles for developing MetS of schizophrenia patients.

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored. Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs. Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1). Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group. Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Background: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. Objective: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). Methods: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. Results: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). Conclusion: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.

Background: Olfactory training is the only evidence-based treatment for post-viral olfactory dysfunction. Smell disorders after SARS-CoV-2 infection have been attributed to neuroinflammatory events within the olfactory bulb and the central nervous system. Therefore, targeting neuroinflammation is one potential strategy for promoting recovery from post-COVID-19 chronic olfactory dysfunction. Palmitoylethanolamide and luteolin (PEA-LUT) are candidate antiinflammatory/ neuroprotective agents. Objective: To investigate recovery of olfactory function in patients treated with PEA-LUT oral supplements plus olfactory training versus olfactory training plus placebo. Methods: Multicenter double-blinded randomized placebo-controlled clinical trial was held. Eligible subjects had prior COVID-19 and persistent olfactory impairment >6 months after follow-up SARS-CoV-2 negative testing, without prior history of olfactory dysfunction or other sinonasal disorders. Participants were randomized to daily oral supplementation with ultramicronized PEA-LUT 770 mg plus olfactory training (intervention group) or olfactory training with placebo (control). Sniffin’ Sticks assessments were used to test the patients at baseline and 90 days. Results: A total of 185 patients, including intervention (130) and control (55) were enrolled. The intervention group showed significantly greater improvement in olfactory threshold, discrimination, and identification scores compared to controls (p=0.0001). Overall, 92% of patients in the intervention group improved versus 42% of controls. Magnitude of recovery was significantly greater in the intervention group versus control (12.8 + 8.2 versus mean 3.2 + 3), with >10-fold higher prevalence of anosmia in control versus intervention groups at the 90-day endpoint. Conclusion: Among individuals with olfactory dysfunction post-COVID-19, combining PEA-LUT with olfactory training resulted in greater recovery of smell than olfactory training alone.