Current Neuropharmacology - Volume 20, Issue 12, 2022

Neonatal arterial ischaemic stroke (NAIS) is caused by focal arterial occlusion and often leads to severe neurological sequelae. Neural deaths after NAIS mainly include necrosis, apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. These neural deaths are mainly caused by upstream stimulations, including excitotoxicity, oxidative stress, inflammation, and death receptor pathways. The current clinical approaches to managing NAIS mainly focus on supportive treatments, including seizure control and anticoagulation. In recent years, research on the pathology, early diagnosis, and potential therapeutic targets of NAIS has progressed. In this review, we summarise the latest progress of research on the pathology, diagnosis, treatment, and prognosis of NAIS and highlight newly potential diagnostic and treatment approaches.

Major depressive disorder (MDD) is a debilitating psychiatric disorder, the third leading global cause of disability. Regarding aetiopathogenetic mechanisms involved in the onset of depressive disorders, the interaction between genetic vulnerability traits and environmental factors is believed to play a major role. Although much is still to be elucidated about the mechanisms through which the environment can interact with genetic background shaping the disease risk, there is a general agreement about a key role of epigenetic marking. In this narrative review, we focused on the association between changes in DNA methylation patterns and MDD or depressive-like phenotype in animal models, as well as mechanisms of response to antidepressant drugs. We discussed studies presenting DNA methylation changes at specific genes of interest and profiling analyses in both patients and animal models of depression. Overall, we collected evidence showing that DNA methylation could not only be considered as a promising epigenetic biomarker of pathology but could also help in predicting antidepressant treatment efficacy. Finally, we discussed the hypothesis that specific changes in DNA methylation signature could play a role in aetiopathogenetic processes as well as in the induction of antidepressant effect.

The arginine vasopressin (AVP), a neurohypophysial hormone, is synthesized within specific sites of the central nervous system and axonally transported to multiple areas, acting as a neurotransmitter/ neuromodulator. In this context, AVP acts primarily through vasopressin receptors A and B and is involved in regulating complex social and cognition behaviors and basic autonomic function. Many earlier studies have shown that AVP as a neuromodulator affects synaptic plasticity. This review updates our current understanding of the underlying molecular mechanisms by which AVP affects synaptic plasticity. Moreover, we discuss AVP modulatory effects on event-related potentials and blood oxygen level-dependent responses in specific brain structures, and AVP effects on the network level oscillatory activity. We aimed at providing an overview of the AVP effects on the brain from the synaptic to the network level.

This review discusses the effects and mechanisms of a ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, mediumprotein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota–gut-brain axis. It also highlights the clinical evidence for the effects of the ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of the ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.

Treatment of Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is currently considered a challenging issue since it causes substantial disability, poor quality of life, and mortality. Despite remarkable progress in advanced conventional therapeutic interventions, the global burden of the disease has nearly doubled, prompting us to assess the riskeffectiveness of different treatment modalities. Each protocol could be considered as the best alternative treatment depending on the patient’s situation. Prescription of levodopa, the most effective available medicine for this disorder, has been associated with many complications, i.e., multiple episodes of "off-time" and treatment resistance. Other medications, which are typically used in combination with levodopa, may have several adverse effects as well. As a result, the therapies that are more in line with human physiology and make the least interference with other pathways are worth investigating. On the other hand, remaining and persistent symptoms after therapy and the lack of effective response to the conventional approaches have raised expectations towards innovative alternative approaches, such as stem cell-based therapy. It is critical to not overlook the unexplored side effects of innovative approaches due to the limited number of research. In this review, we aimed to compare the efficacy and risk of advanced therapies with innovative cell-based and stemcell- based modalities in PD patients. This paper recapitulated the underlying factors/conditions, which could lead us to more practical and established therapeutic outcomes with more advantages and few complications. It could be an initial step to reconsider the therapeutic blueprint for patients with Parkinson’s disease.

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

Background: mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of “monogenic” forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Objective: Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. Methods: Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. Results: Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. Conclusion: These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy.

Background: GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients. Methods: Three weeks after MK801 administration (0.5 mg kg^-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2. Results: MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01). Conclusion: Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients’ symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.

Objectives: There is limited evidence about the factors influencing antidepressant (AD) prescription for the treatment of major depressive disorder (MDD) in Real World clinical practice in Italy. In this retrospective, population-based study, we set out to describe a patient cohort initiated on AD treatment for MDD and investigate the possible predictors of different AD prescriptions in the primary care setting. Methods: Patients with a diagnosis of MDD who received an initial prescription of one of 11 selected ADs between 1-Apr-2017 and 31-Mar-2019 (index date) were identified from primary care electronic medical records in the Longitudinal Patient Database. Patients prescribed ≥1 AD in the 12 months before the index date were excluded. Results were stratified by AD molecule. Multivariable logistic regression models estimated the association between patients’ demographic, clinical factors, and choice of AD molecule. Results: The study cohort comprised 8,823 patients (67.1% female; mean age 61.6 years). Previous AD treatments (prescribed in the 10 years before the index date) had been received by 46.6% of patients (non-naïve patients). The most commonly reported psychiatric and medical comorbidities reported in the 12 months before the index date were anxiety (8.4%) and hypertension (41.9%), respectively. Patients’ age was a significant predictor of AD molecule prescribed at index date in eight of the 11 molecules investigated, while patients’ gender influenced clinician prescribing bupropion, citalopram, fluoxetine, fluvoxamine, sertraline, and vortioxetine. Conclusion: Results from this Real World study provide useful information for clinicians on the clinical factors influencing AD prescription in patients treated for MDD in primary care.

Background: The Covid 19 pandemic might have impacted response to drug treatment in major depressive episode (MDE). We compared responses to three different antidepressant drugs, i.e., vortioxetine, sertraline, and trazodone, in outpatients with MDE during Major Depressive Disorder (MDD), Bipolar Disorder (BD), or schizophrenia and related psychoses (SSOPDs) during two time periods, i.e., before and after suffering Covid-19-related trauma. Methods: We conducted an observational study on clinically stabilised for at least 6 months outpatients with MDE during the course of MDD (N=58), BD (N=33), or SSOPDs (N=51). Patients, whose baseline assessments of Montgomery-Åsberg Rating Scale (MADRS), Hamilton Anxiety Rating Scale (Ham-A), Brief Psychiatric Rating Scale (BPRS), Visual Analogue Scale for Craving (VAS-crav) and World Health Organization Quality of Life, Brief version (WHOQOL-BREF) were available, were recruited at the time they suffered Covid-19-related traumas. Fifty patients, prior to the pandemic, when they were clinically stable, were treated with 15 mg/die vortioxetine, 44 with 450 mg/die trazodone, and 48 with 150 mg/die sertraline. After experiencing a major Covid-19-related personal trauma, patients showed clinical worsening which required dosage adjustment (20 mg/day vortioxetine; 600 mg/day trazodone, and 200 mg/day sertraline) and, for some of them, hospitalisation. Scores on the MADRS, Ham-A, BPRS, VAS-crav and WHOQOL-BREF were compared drug-wise and genderwise with Student’s t test for continuous variables and Χ² for categorical variables. Results: The sample consisted of 142 outpatients (age, mean 39.63 ± 16.84; 70 men and 72 women); women were older than men (mean age 43.18 ± 17.61 vs. 35.98 ± 15.30; p=0.01). The two genders did not differ on other variables. For all treatments, worsening symptoms were observed at the time of trauma, followed by slow recovery with treatment readjustment. Trauma-related worsening in patients on vortioxetine was less intense than patients on the other two antidepressants and recovery was faster. All drugs were associated with an improvement in QoL. The vortioxetine group showed a lower hospitalisation rate (24%) than sertraline (35.4%) and trazodone (38.6%), but this was not significant (p=0.27). Conclusion: All drugs improved symptoms of Covid-19 trauma in patients with MDE, with vortioxetine showing a small advantage. No differences between vortioxetine, sertraline and trazodone were found as concerning the need for hospitalisation.