Current Neuropharmacology - Volume 21, Issue 3, 2023

Background: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. Objective: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. Methods: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. Results: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms’ stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. Conclusion: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Tumor-associated macrophages (TAMs), the most plastic cells of the hematopoietic system, exhibit increased tumor-infiltrating properties and functional heterogeneity depending on tumor type and associated microenvironment. TAMs constitute a major cell type of cancer-related inflammation, commonly enhancing tumor growth. They are profoundly involved in glioma pathogenesis, contributing to many cancer hallmarks such as angiogenesis, survival, metastasis, and immunosuppression. Efficient targeting of TAMs presents a promising approach to tackle glioma progression. Several targeting options involve chemokine signaling axes inhibitors and antibodies, antiangiogenic factors, immunomodulatory molecules, surface immunoglobulins blockers, receptor and transcription factor inhibitors, as well as microRNAs (miRNAs), administered either as standalone or in combination with other conventional therapies. Herein, we provide a critical overview of current therapeutic approaches targeting TAMs in gliomas with the promising outcome.

Variant Transthyretin Amyloidosis (ATTRv) neuropathy is an adult-onset, autosomal dominant, lethal, multisystemic disease due to the deposition of mutated transthyretin (TTR) in various organs, commonly involving the peripheral nerves and the heart. Circulating TTR tetramers are unstable due to the presence of mutated TTR and dissociate into monomers, which misfold and form amyloid fibrils. Although there are more than 140 mutations in the TTR gene, the p.Val50Met mutation is by far the commonest. In the typical, early-onset cases, it presents with a small sensory fibre and autonomic, length-dependent, axonal neuropathy, while in late-onset cases, it presents with a lengthdependent sensorimotor axonal neuropathy involving all fibre sizes. Treatment is now available and includes TTR stabilizers, TTR amyloid removal as well as gene silencing, while gene editing therapies are on the way. Its timely diagnosis is of paramount importance for a better prognosis.

Background: The mutated VAPBP56S (vesicle B associated membrane protein – P56S) protein has been described in a Brazilian family and classified as Amyotrophic Lateral Sclerosis type 8 (ALS8). Objective: We aimed to study altered biochemical and immunological parameters in cells from ALS8 patients to identify possible biomarkers or therapeutic targets. Methods: Wild-type VAPB, VAPBP56S, mTOR, proinflammatory cytokines, and oxidant/reducing levels in serum, leucocytes, and cellular lysate from ALS8 patients and health Controls were performed by ELISA, fluorimetry, and spectrophotometry. Results: Our results showed similar levels of mutant and wild-type VAPB in serum and intracellular lysate (p > 0.05) when ALS8 patients and Controls were compared. IL-1β, IL-6, and IL-18 levels in patients and Controls showed no difference, suggesting an absence of peripheral inflammation (p > 0.05). Oxidative metabolic response, assessed by mitochondrial ROS production, and reductive response by MTT reduction, were higher in the ALS8 group compared to Controls (p < 0.05), although not characterizing typical oxidative stress in ALS8 patients. Total mTOR levels (phosphorylated or non-phosphorylated) of ALS8 patients were significantly lower in serum and higher in intracellular lysate than the mean equivalents in Controls (p < 0.05). A similar result was observed when we quantified the phosphorylated protein (p < 0.05). Conclusion: We demonstrate the possibility of using these biochemical and immunological parameters as potential therapeutic targets or biomarkers. Furthermore, by hypothesis, we suggest a hormetic response in which both VAPB forms could coexist in different proportions throughout life. The mutated VAPBP56S production would increase with aging and predominate over the wild-type VAPB levels, determining the onset of symptoms and aggravating the disease.

Blood-Brain Barrier (BBB) acts as a highly impermeable barrier, presenting an impediment to the crossing of most classical drugs targeted for neurodegenerative diseases including Parkinson's disease (PD). About the nature of drugs and other potential molecules, they impose unavoidable doserestricted limitations eventually leading to the failure of therapy. However, many advancements in formulation technology and modification of delivery approaches have been successful in delivering the drug to the brain in the therapeutic window. The nose to the brain (N2B) drug delivery employing the nanoformulation, is one such emerging delivery approach, overcoming both classical drug formulation and delivery-associated limitations. This latter approach offers increased bioavailability, greater patient acceptance, lesser metabolic degradation of drugs, circumvention of BBB, ample drug loading along with the controlled release of the drugs. In N2B delivery, the intranasal (IN) route carries therapeutics firstly into the nasal cavity followed by the brain through olfactory and trigeminal nerve connections linked with nasal mucosa. The N2B delivery approach is being explored for delivering other biologicals like neuropeptides and mitochondria. Meanwhile, this N2B delivery system is associated with critical challenges consisting of mucociliary clearance, degradation by enzymes, and drug translocations by efflux mechanisms. These challenges finally culminated in the development of suitable surfacemodified nano-carriers and Focused- Ultrasound-Assisted IN as FUS-IN technique which has expanded the horizons of N2B drug delivery. Hence, nanotechnology, in collaboration with advances in the IN route of drug administration, has a diversified approach for treating PD. The present review discusses the physiology and limitation of IN delivery along with current advances in nanocarrier and technical development assisting N2B drug delivery.

Brain disorders are a prevalent and rapidly growing problem in the medical field as they adversely affect the quality of life of a human. With an increase in life expectancy, it has been reported that diseases like Alzheimer’s, Parkinson’s, stroke and brain tumors, along with neuropsychological disorders, are also being reported at an alarmingly high rate. Despite various therapeutic methods for treating brain disorders, drug delivery to the brain has been challenging because of a very complex Blood Brain Barrier, which precludes most drugs from entering the brain in effective concentrations. Nano-carrier-based drug delivery systems have been reported widely by researchers to overcome this barrier layer. These systems due to their small size, offer numerous advantages; however, their short residence time in the body owing to opsonization hinders their success in vivo. This review article focuses on the various aspects of modifying the surfaces of these nano-carriers with polymers, surfactants, protein, antibodies, cell-penetrating peptides, integrin binding peptides and glycoproteins such as transferrin & lactoferrin leading to enhanced residence time, desirable characteristics such as the ability to cross the blood-brain barrier (BBB), increased bioavailability in regions of the brain and targeted drug delivery.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease with a significant public health burden. It is characterized by the gradual degeneration of dopamine neurons in the central nervous system. Although symptomatic pharmacological management remains the primary therapeutic method for PD, clinical experience reveals significant inter-individual heterogeneity in treatment effectiveness and adverse medication responses. The mechanisms behind the observed interindividual variability may be elucidated by investigating the role of genetic variation in human-to-human variances in medication responses and adverse effects. Objective: This review aims to explore the impact of gene polymorphism on the efficacy of antiparkinsonian drugs. The identification of factors associated with treatment effectiveness variability might assist the creation of a more tailored pharmacological therapy with higher efficacy, fewer side outcomes, and cheaper costs. Methods: In this review, we conducted a thorough search in databases such as PubMed, Web of Science, and Google Scholar, and critically examined current discoveries on Parkinson's disease pharmacogenetics. The ethnicity of the individuals, research methodologies, and potential bias of these studies were thoroughly compared, with the primary focus on consistent conclusions. Results: This review provides a summary of the existing data on PD pharmacogenetics, identifies its limitations, and offers insights that may be beneficial for future research. Previous studies have investigated the impact of gene polymorphism on the effectiveness and adverse effects of levodopa. The trendiest genes are the COMT gene, DAT gene, and DRD2 gene. However, limited study on other anti-Parkinson's drugs has been conducted. Conclusion: Therefore, In order to develop an individualized precision treatment for PD, it is an inevitable trend to carry out multi-center, prospective, randomized controlled clinical trials of PD pharmacogenomics covering common clinical anti-PD drugs in large, homogeneous cohorts.

Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuronglia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.

Despite being classified as a movement disorder, Parkinson’s disease (PD) is characterized by a wide range of non-motor symptoms that significantly affect the patients' quality of life. However, clear evidence-based therapy recommendations for non-motor symptoms of PD are uncommon. Animal models of PD have previously been shown to be useful for advancing the knowledge and treatment of motor symptoms. However, these models may provide insight into and assess therapies for non-motor symptoms in PD. This paper highlights non-motor symptoms in preclinical models of PD and the current position regarding preclinical therapeutic approaches for these non-motor symptoms. This information may be relevant for designing future preclinical investigations of therapies for nonmotor symptoms in PD.

Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA.

The vascular system plays a critical role in human physiology and diseases. It is a complex subject to study using in vitro models due to its dynamic and three-dimensional microenvironment. Microfluidic technology has recently become a popular technology in various biological fields for its advantages in mimicking complex microenvironments to an extent not achievable by more conventional platforms. Microfluidic technologies can reproduce different vascular system-related structures and functions that can be utilized for drug development and human diseases studies. Herein, we first review the relevant structural and functional vascular biology systems of various organ systems and then the fabrication methods to reproduce these vascular districts. We provide a thorough review of the latest achievement in vascular organ-on-chip modeling specific to lung, heart, and the brain microvasculature for drug screening and the study of human disorders.

As the first peripheral immune cells to enter the brain after ischemic stroke, neutrophils are important participants in stroke-related neuroinflammation. Neutrophils are quickly mobilized from the periphery in response to a stroke episode and cross the blood-brain barrier to reach the ischemic brain parenchyma. This process involves the mobilization and activation of neutrophils from peripheral immune organs (including the bone marrow and spleen), their chemotaxis in the peripheral blood, and their infiltration into the brain parenchyma (including disruption of the blood-brain barrier, inflammatory effects on brain tissue, and interactions with other immune cell types). In the past, it was believed that neutrophils aggravated brain injuries through the massive release of proteases, reactive oxygen species, pro-inflammatory factors, and extracellular structures known as neutrophil extracellular traps (NETs). With the failure of early clinical trials targeting neutrophils and uncovering their underlying heterogeneity, our view of their role in ischemic stroke has become more complex and multifaceted. As neutrophils can be divided into N1 and N2 phenotypes in tumors, neutrophils have also been found to have similar phenotypes after ischemic stroke, and play different roles in the development and prognosis of ischemic stroke. N1 neutrophils are dominant during the acute phase of stroke (within three days) and are responsible for the damage to neural structures via the aforementioned mechanisms. However, the proportion of N2 neutrophils gradually increases in later phases, and this has a beneficial effect through the release of anti-inflammatory factors and other neuroprotective mediators. Moreover, the N1 and N2 phenotypes are highly plastic and can be transformed into each other under certain conditions. The pronounced differences in their function and their high degree of plasticity make these neutrophil subpopulations promising targets for the treatment of ischemic stroke.

Adult neurogenesis deficiency has been proposed to be a common hallmark in different age-related neurodegenerative diseases. The administration of flavonoids is currently reported as a potentially beneficial strategy for preventing brain aging alterations, including adult neurogenesis decline. Flavonoids are a class of plant-derived dietary polyphenols that have drawn attention for their neuroprotective and pro-cognitive effects. Although they undergo extensive metabolism and localize in the brain at low concentrations, flavonoids are now believed to improve cerebral vasculature and interact with signal transduction cascades involved in the regulation of adult neurogenesis. Furthermore, many dietary flavonoids have been shown to reduce oxidative stress and neuroinflammation, improving the neuronal microenvironment where adult neurogenesis occurs. The overall goal of this review is to summarize the evidence supporting the role of flavonoids in modulating adult neurogenesis as well as to highlight how these dietary agents may be promising candidates in restoring healthy brain function during physiological and pathological aging.

Intracerebral hemorrhage (ICH) is a neurological disease with high mortality and disability. Recent studies showed that white matter injury (WMI) plays an important role in motor dysfunction after ICH. WMI includes WMI proximal to the lesion and WMI distal to the lesion, such as corticospinal tract injury located at the cervical enlargement of the spinal cord after ICH. Previous studies have tended to focus only on gray matter (GM) injury after ICH, and fewer studies have paid attention to WMI, which may be one of the reasons for the poor outcome of previous drug treatments. Microglia and astrocyte-mediated neuroinflammation are significant mechanisms responsible for secondary WMI following ICH. The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation, has been shown to exacerbate neuroinflammation and brain injury after ICH. Moreover, NLRP3 inflammasome is activated in microglia and astrocytes and exerts a vital role in microglia and astrocytes-mediated neuroinflammation. We speculate that NLRP3 inflammasome activation is closely related to the polarization of microglia and astrocytes and that NLRP3 inflammasome activation may exacerbate WMI by polarizing microglia and astrocytes to the pro-inflammatory phenotype after ICH, while NLRP3 inflammasome inhibition may attenuate WMI by polarizing microglia and astrocytes to the anti-inflammatory phenotype following ICH. Therefore, NLRP3 inflammasome may act as leveraged regulatory fulcrums for microglia and astrocytes polarization to modulate WMI and WM repair after ICH. This review summarized the possible mechanisms by which neuroinflammation mediated by NLRP3 inflammasome exacerbates secondary WMI after ICH and discussed the potential therapeutic targets.

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disease resulting from the experience or witnessing of traumatic events. Persistent PTSD symptoms impair patients’ daily quality of life, jeopardizing sleep, mood, sociability, and arousal. Recommended psychological or pharmacological interventions are effective only in a small portion of patients and often lead to relapse. Thus, there is a critical need to address a lack of advancement in the treatment of PTSD. The combination of psychological interventions, aimed at facilitating the extinction of the traumatic memory, and pharmacological medications, represents a promising tool for PTSD treatment. Timely use of psychotherapy in conjunction with pharmacological treatments, rather than monotherapy, could thus determine a synergistic effect by potentiating the effects of psychological interventions. In such a scenario, drugs that modulate cognitive processes involved in the development and/or persistence of post-traumatic symptomatology could be of great help to improve the outcome of psychotherapies and patients' prognosis. The purpose of the present article is to review the current data available from clinical trials on combined pharmacological treatments with psychological interventions in PTSD therapy. An overview of findings from animal studies that prompted clinical research is also discussed.

Background: Status epilepticus (SE) is a serious neurological disease that manifests as prolonged seizures that last more than 5 minutes and between such episodes, patients do not regain consciousness. It can result in cognitive defects, brain damage, or even death. It is commonly known that one of the causes can be an inflammatory process, but here we will focus on inflammation as a result of new onset refractory status epilepticus and, related to this, new promising forms of SE treatment. Particular emphasis has been focused on new-onset refractory status epilepticus (NORSE). Methods: Based on public research databases, drugs with anti-inflammatory activity – commonly used in different spheres of medicine – have been reviewed as potentially treating status epilepticus. Results: There is seizable clinical research suggesting that drugs that decrease inflammatory processes might be effective in terminating status epilepticus. Conclusion: There is growing evidence showing that adding anti-inflammatory drugs to basic antiepileptic treatment enhances the efficiency of the therapeutic process, with special potential in NORSE cases.

Cannabinoids are compounds isolated from cannabis and are also widely present in both nervous and immune systems of animals. In recent years, with in-depth research on cannabinoids, their clinical medicinal value has been evaluated, and many exciting achievements have been continuously accumulating, especially in the field of neurodegenerative disease. Alzheimer's disease is the most common type of neurodegenerative disease that causes dementia and has become a global health problem that seriously impacts human health today. In this review, we discuss the therapeutic potential of cannabinoids for the treatment of Alzheimer’s disease. How cannabinoids act on different endocannabinoid receptor subtypes to regulate Alzheimer’s disease and the roles of the endocannabinoid system in Alzheimer’s disease are outlined, and the underlying mechanisms are discussed. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to Alzheimer’s disease and discuss the potential usefulness of cannabinoids in the clinical treatment of Alzheimer’s disease.