Current Neuropharmacology - Volume 21, Issue 10, 2023

Neuroinflammation is a common feature of diverse nervous system pathologies. In many instances, it begins at an early stage of the disease, paving the way for further exacerbations. The main drivers of neuroinflammation are brain-resident glial cells, such as microglia and astrocytes. Microglia are the primary responders to any insult to the brain parenchyma, translating the signals into diverse molecules. These molecules derived from microglia can regulate the stimuli-dependent reactivity of astrocytes. Once activated, astrocytes in turn, can control microglia phenotypes. Recent evidence indicates that the crosstalk between these glial cells plays an important role in delaying or accelerating neuroinflammation and overall disease progression. To date, various molecules have been recognized as key mediators of the bidirectional communication between microglia and astrocytes. The current review aims to discuss the novel molecules identified recently, which play a critical role in interglial crosstalk, highlighting their therapeutic potential.

In recent years, increasing attention has been paid to the role of physical factors in biological processes. This direction was ultimately confirmed by the recent 2021 Nobel Prize in medicine and physiology awarded in ½ to Ardem Patapoutian for his discovery of Piezo1 and Piezo2 mechanosensitive receptors. Among them, Piezo2 is responsible for sensing touch, while Piezo1 is engaged in a variety of mechanotransduction events. Piezo1 is expressed in various central nervous system cells, while its expression may be affected in the course of various pathological conditions. Recently, thanks to the development of Piezo1 modulators (i.e. Yoda1, Jedi1/2 and Dooku2), it is possible to study the role of Piezo1 in the pathogenesis of various neurological diseases including ischemia, glioma, and age-related dementias. The results obtained in this field suggest that proper modulation of Piezo1 receptor might be beneficial in the course of various neurological diseases.

Alzheimer’s disease (AD) and type 2 diabetes mellitus (DM) are more prevalent with ageing and cause a substantial global socio-economic burden. The biology of these two conditions is well elaborated, but whether AD and type 2 DM arise from coincidental roots in ageing or are linked by pathophysiological mechanisms remains unclear. Research findings involving animal models have identified mechanisms shared by both AD and type 2 DM. Deposition of β-amyloid peptides and formation of intracellular neurofibrillary tangles are pathological hallmarks of AD. Type 2 DM, on the other hand, is a metabolic disorder characterised by hyperglycaemia and insulin resistance. Several studies show that improving type 2 DM can delay or prevent the development of AD, and hence, prevention and control of type 2 DM may reduce the risk of AD later in life. Alpha-glucosidase is an enzyme that is commonly associated with hyperglycaemia in type 2 DM. However, it is uncertain if this enzyme may play a role in the progression of AD. This review explores the experimental evidence that depicts the relationship between dysregulation of glucose metabolism and AD. We also delineate the links between alpha-glucosidase and AD and the potential role of alpha-glucosidase inhibitors in treating AD.

Epilepsy is defined as spontaneous recurrent seizures in the brain. There is increasing evidence that inflammatory mediators and immune cells are involved in epileptic seizures. As more research is done on inflammatory factors and immune cells in epilepsy, new targets for the treatment of epilepsy will be revealed. The Janus kinase-signal transducer and transcriptional activator (JAKSTAT) signaling pathway is strongly associated with many immune and inflammatory diseases, At present, more and more studies have found that the JAK-STAT pathway is involved in the development and development of epilepsy, indicating the JAK-STAT pathway’s potential promise as a target in epilepsy treatment. In this review, we discuss the composition, activation, and regulation of the JAK-STAT pathway and the relationship between the JAK-STAT pathway and epilepsy. In addition, we summarize the common clinical inhibitors of JAK and STAT that we would expect to be used in epilepsy treatment in the future.

Hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1) is predominantly expressed in neurons from the neocortex and hippocampus, two important regions related to epilepsy. Both animal models for epilepsy and epileptic patients show decreased HCN1 expression and HCN1-mediated Ih current. It has been shown in neuroelectrophysiological experiments that a decreased Ih current can increase neuronal excitability. However, some studies have shown that blocking the Ih current in vivo can exert antiepileptic effects. This paradox raises an important question regarding the causal relationship between HCN1 alteration and epileptogenesis, which to date has not been elucidated. In this review, we summarize the literature related to HCN1 and epilepsy, aiming to find a possible explanation for this paradox, and explore the correlation between HCN1 and the mechanism of epileptogenesis. We analyze the alterations in the expression and distribution of HCN1 and the corresponding impact on brain function in epilepsy. In addition, we also discuss the effect of blocking Ih on epilepsy symptoms. Addressing these issues will help to inspire new strategies to explore the relationship between HCN1 and epileptogenesis, and ultimately promote the development of new targets for epilepsy therapy.

Cerebral ischemic injury, one of the leading causes of morbidity and mortality worldwide, triggers various central nervous system (CNS) diseases, including acute ischemic stroke (AIS) and chronic ischemia-induced Alzheimer's disease (AD). Currently, targeted therapies are urgently needed to address neurological disorders caused by cerebral ischemia/reperfusion injury (CI/RI), and the emergence of neutrophil extracellular traps (NETs) may be able to relieve the pressure. Neutrophils are precursors to brain injury following ischemic stroke and exert complicated functions. NETs extracellularly release reticular complexes of neutrophils, i.e., double-stranded DNA (dsDNA), histones, and granulins. Paradoxically, NETs play a dual role, friend and foe, under different conditions, for example, physiological circumstances, infection, neurodegeneration, and ischemia/reperfusion. Increasing evidence indicates that NETs exert anti-inflammatory effects by degrading cytokines and chemokines through protease at a relatively stable and moderate level under physiological conditions, while excessive amounts of NETs release (NETosis) irritated by CI/RI exacerbate the inflammatory response and aggravate thrombosis, disrupt the blood-brain barrier (BBB), and initiates sequential neuron injury and tissue damage. This review provides a comprehensive overview of the machinery of NETs formation and the role of an abnormal cascade of NETs in CI/RI, as well as other ischemia-induced neurological diseases. Herein, we highlight the potential of NETs as a therapeutic target against ischemic stroke that may inspire translational research and innovative clinical approaches.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), cerebral amyloid angiopathy (CAA), and Huntington’s disease (HD) are characterized by cognitive and motor dysfunctions and neurodegeneration. These diseases have become more severe over time and cannot be cured currently. Until now, most treatments for these diseases are only used to relieve the symptoms. Taxifolin (TAX), 3,5,7,3,4-pentahydroxy flavanone, also named dihydroquercetin, is a compound derived primarily from Douglas fir and Larix gemelini. TAX has been confirmed to exhibit various pharmacological activities, including anti-inflammation, anti-cancer, anti-virus, and regulation of oxidative stress effects. In the central nervous system, TAX has been demonstrated to inhibit Aβ fibril formation, protect neurons and improve cerebral blood flow, cognitive ability, and dyskinesia. At present, TAX is only applied as a health additive in clinical practice. This review aimed to summarize the application of TAX in neurodegenerative diseases and the underlying neuroprotective mechanisms, such as suppressing inflammation, attenuating oxidative stress, preventing Aβ protein formation, maintaining dopamine levels, and thus reducing neuronal loss.

The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

Advances in stroke treatment have resulted in a dramatic reduction in stroke mortality. Nevertheless, poststroke seizures and epilepsy are issues of clinical importance affecting survivors. Additionally, stroke is the most common cause of epilepsy in older adults. Although numerous antiseizure medications exist, studies are needed to provide robust evidence of the efficacy and tolerability of these medicines for treating poststroke seizures and epilepsy. Crucially, the newer generations of antiseizure medications require testing. Lacosamide, a third-generation antiseizure medication approved for treating localization-related epilepsy, has a novel mechanism of selectively enhancing the slow inactivation of sodium channels. This literature review evaluated whether lacosamide is effective and safe for the treatment of poststroke seizures and epilepsy. This review critically analyzed studies published in major academic databases (Pubmed, Embase, and Cochrane Library) from inception through June 2022 regarding the interaction of lacosamide with poststroke seizures and epilepsy. We included clinical prospective, retrospective, and case studies on patients with poststroke seizure and epilepsy, lacosamide as a treatment for seizures, neuroprotection in animal models of seizures, and the safety of lacosamide when coadministering anticoagulants. Clinical studies revealed lacosamide to be an effective antiseizure medication with high efficacy and tolerability in patients with poststroke seizures and epilepsy. In animal models, lacosamide proved effective at seizure reduction and neuroprotection. Pharmacokinetic studies demonstrated the safety of lacosamide when coadministering conventional and new anticoagulants. The literature suggests that Lacosamide is a promising candidate antiseizure medication for patients with poststroke seizures and epilepsy.

Objective: Severe neurologic complications after spinal anesthesia are rare but highly distressing, especially in pregnant women. Bupivacaine is widely used in spinal anesthesia, but its neurotoxic effects have gained attention. Methods: Furthermore, the etiology of bupivacaine-mediated neurotoxicity in obstetric patients remains unclear. Female C57BL/6 mice were intrathecally injected with 0.75% bupivacaine on the 18th day of pregnancy. We used immunohistochemistry to examine DNA damage after bupivacaine treatment in pregnant mice and measured γ-H2AX (Ser139) and 8-OHdG in the spinal cord. A PARP-1 inhibitor (PJ34) and autophagy inhibitor (3-MA) were administered with bupivacaine in pregnant mice. Parp-1^flox/flox mice were crossed with Nes-Cre transgenic mice to obtain neuronal conditional knockdown mice. Then, LC3B and P62 staining were performed to evaluate autophagic flux in the spinal cords of pregnant wild-type (WT) and Parp-1^-/- mice. We performed transmission electron microscopy (TEM) to evaluate autophagosomes. Results: The present study showed that oxidative stress-mediated DNA damage and neuronal injury were increased after bupivacaine treatment in the spinal cords of pregnant mice. Moreover, PARP-1 was significantly activated, and autophagic flux was disrupted. Further studies revealed that PARP-1 knockdown and autophagy inhibitors could alleviate bupivacaine-mediated neurotoxicity in pregnant mice. Conclusion: Bupivacaine may cause neuronal DNA damage and PARP-1 activation in pregnant mice. PARP-1 further obstructed autophagic flux and ultimately led to neurotoxicity.

Objectives: There is overwhelming evidence of the relationship between smoking and schizophrenia (SZ). Tobacco smoke is considered to ameliorate the symptoms and reduce the side effects of antipsychotics in SZ patients. However, the underlying biological mechanism by which tobacco smoke improves symptoms in SZ remains unclear. This study was designed to examine the effects of tobacco smoke on antioxidant enzyme activities and psychiatric symptoms after receiving 12-week risperidone monotherapy. Methods: Two hundred and fifteen antipsychotic-naïve first-episode (ANFE) patients were recruited and treated with risperidone for 3 months. The severity of the patient’s symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS) at baseline and at post-treatment. Plasma SOD, GSH-Px, and CAT activities were determined at baseline and follow-up. Results: Relative to nonsmoking patients with ANFE SZ, patients who smoked had higher baseline CAT activity. In addition, among non-smokers with SZ, baseline GSH-Px was associated with clinical symptom improvement, while baseline CAT was associated with positive symptom improvement in smokers with SZ. Conclusion: Our findings demonstrate that smoking affects the predictive role of baseline SOD, GSHPx, and CAT activities on clinical symptom improvement in patients with SZ.

Background: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a “don't eat me” signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood. Methods: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo. Results: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68⁺ macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro. In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot. Conclusion: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma.