Current Neuropharmacology - Volume 19, Issue 11, 2021

Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition found in 5-10% of school-age children and in 2-5% of adults. Stimulants affecting the dopaminergic, noradrenergic and/or serotonergic systems are commonly used for treatment in children and adults, including women of childbearing age. The data on the effects of stimulants (methylphenidate and amphetamines) in pregnancy are generally reassuring, but methylphenidate might slightly increase the rate of cardiac malformations and of spontaneous abortions, while amphetamines might slightly increase the risk for premature birth, low birth weight and other pregnancy complications. Bupropion, a dopamine and norepinephrine reuptake inhibitor, when used as an antidepressant, appears to be safe in pregnancy. The data on the use of atomoxetine, guanfacine and clonidine in pregnancy are scarce. Importantly, there are practically no data on the long-term neurodevelopmental effects of most of these drugs. The published data on the development of children born to methamphetamineabusing women may be misleading since these women generally use other drugs, including alcohol, and the home environment where the child is raised may not be optimal. The treating physician should judge the need for treatment during pregnancy in relation to the severity of the clinical symptoms. If needed, methylphenidate is preferred over amphetamines because breast feeding is possible. If one uses non-stimulant medications, bupropion seems to be the preferred drug.

It is challenging to balance the fetal risks associated with the use of antiepileptic drugs (AEDs) against maternal and fetal risks of seizure worsening, and therefore it is very important to define and distinguish the possible risks entailed by different AEDs. This paper aims to undertake a comprehensive review regarding the possible risks of four classical (phenytoin, carbamazepine, phenobarbital, and valproate) and two newer (lamotrigine and levetiracetam) AEDs during pregnancy. The review focuses on major and organ-specific malformations, dose-dependent risks, mono vs polytherapy, and clinical pharmacokinetics. A discussion regarding the safety of AED use during breastfeeding is also provided.

Exposure in the womb to antiseizure medications and their potential impact on the brain of the developing child has long been researched. Despite this long period of interest, this review highlights that above the well-known risks associated with valproate exposure, there are more data required for conclusions regarding all other antiseizure medications. Limited experience with phenytoin and phenobarbital in monotherapy makes clearly defining the risk to later child postnatal functioning difficult, although the evidence of an impact is stronger for phenobarbital than for phenytoin. The widely prescribed lamotrigine is limited in its investigation in comparison to unexposed control children, and whilst it has been demonstrated to carry a lower risk than valproate for certain outcomes, whether it is associated with a more moderate impact on wider aspects of neurodevelopmental functioning is still to be understood. Data for levetiracetam, topiramate and oxcarbazepine are too limited to confidently draw conclusions for most neurodevelopmental outcomes. This slow accumulation of evidence impacts on the safest use of medications in pregnancy and makes counseling women regarding the risks and benefits of specific antiseizure medications difficult. Improved focus, funding, and research methodologies are urgently needed.

Progressive neurological damage after brain or spinal cord trauma causes loss of motor function and treatment is very limited. Clotting and hemorrhage occur early after spinal cord (SCI) and traumatic brain injury (TBI), inducing aggressive immune cell activation and progressive neuronal damage. Thrombotic and thrombolytic proteases have direct effects on neurons and glia, both healing and also damaging bidirectional immune cell interactions. Serine proteases in the thrombolytic cascade, tissue- and urokinase-type plasminogen activators (tPA and uPA), as well as the clotting factor thrombin, have varied effects, increasing neuron and glial cell growth and migration (tPA), or conversely causing apoptosis (thrombin) and activating inflammatory cell responses. tPA and uPA activate plasmin and matrix metalloproteinases (MMPs) that break down connective tissue allowing immune cell invasion, promoting neurite outgrowth. Serine proteases also activate chemokines. Chemokines are small proteins that direct immune cell invasion but also mediate neuron and glial cell communication. We are investigating a new class of therapeutics, virus-derived immune modulators; One that targets coagulation pathway serine proteases and a second that inhibits chemokines. We have demonstrated that local infusion of these biologics after SCI reduces inflammation providing early improved motor function. Serp-1 is a Myxomavirus-derived serine protease inhibitor, a serpin, that inhibits both thrombotic and thrombolytic proteases. M-T7 is a virus-derived chemokine modulator. Here we review the roles of thrombotic and thrombolytic serine proteases and chemoattractant proteins, chemokines, as potential therapeutic targets for SCI. We discuss virus-derived immune modulators as treatments to reduce progressive inflammation and ongoing nerve damage after SCI.

Background: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. Moreover, its role in epileptogenesis remains unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. Methods: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". Results: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. Conclusion: This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to elucidate the role of ASIC1a in epilepsy further.

Over the decades, various interventions have been developed and utilized to treat epilepsy. However, the majority of epileptic patients are often first prescribed anti-epileptic drugs (AED), now known as anti-seizure drugs (ASD), as the first line of defense to suppress their seizures and regain their quality of life. ASDs exert their anti-convulsant effects through various mechanisms of action, including regulation of ion channels, blocking glutamate-mediated stimulating neurotransmitter interaction, and enhancing the inhibitory GABA transmission. About one-third of epileptic patients are often resistant to anti-convulsant drugs, while others develop numerous side effects, which may lead to treatment discontinuation and further deterioration of quality of life. Common side effects of ASDs include headache, nausea and dizziness. However, more adverse effects, such as auditory and visual problems, skin problems, liver dysfunction, pancreatitis and kidney disorders may also be witnessed. Some ASDs may even result in life-threatening conditions as well as serious abnormalities, especially in patients with comorbidities and in pregnant women. Nevertheless, some clinicians had observed a reduction in the development of side effects post individualized ASD treatment. This suggests that a careful and well-informed ASD recommendation to patients may be crucial for an effective and side-effect-free control of their seizures. Therefore, this review aimed to elucidate the anticonvulsant effects of ASDs as well as their side effect profile by discussing their mechanism of action and reported adverse effects based on clinical and preclinical studies, thereby providing clinicians with a greater understanding of the safety of current ASDs.

Background: Alzheimer's disease (AD) affects several people worldwide and has devastating impacts on society with a limited number of approaches for its pharmacological treatment. The main causes of AD are not clear yet. However, the formation of senile plaques, neurofibrillary tangles, hyper-phosphorylation of tau protein, and disruption of redox homeostasis may cause AD. These causes have a positive correlation with oxidative stress, producing reactive ions, which are responsible for altering the physiological condition of the body. Conclusion: Ongoing research recommended the use of phytochemicals as acetylcholinesterase inhibitors to hinder the onset and progression of AD. The natural compound structures, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids have anti-inflammatory, antioxidant, and anti-amyloidogenic properties. The purpose of this article is to provide a brief introduction to AD along with the use of natural compounds as new therapeutic approaches for its management.

Neurodegenerative diseases (ND), as a group of central nervous system (CNS) disorders, are among the most prominent medical problems of the 21st century. They are often associated with considerable disability, motor dysfunction and dementia and are more common in the aged population. ND imposes a psychologic, economic and social burden on the patients and their families. Currently, there is no effective treatment for ND. Since many ND result from the gain of function of a mutant allele, small interference RNA (siRNA) can be a potential therapeutic agent for ND management. Based on the RNA interference (RNAi) approach, siRNA is a powerful tool for modulating gene expression through gene silencing. However, there are some obstacles in the clinical application of siRNA, including unfavorable immune response, off-target effects, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system. Since there are some issues related to siRNA delivery routes, in this review, we focus on the application of siRNA in the management of ND treatment from 2000 to 2020.

Autophagy and phagocytosis are two important endogenous lysosomal dependent clearing systems in the organism. In some neurological disorders, excessive autophagy or dysfunctional phagocytosis has been shown to contribute to brain injury. Recent studies have revealed that there are underlying interactions between these two processes. However, different studies show inconsistent results for the contribution of autophagy to the phagocytic process in diverse phagocytes and relatively little is known about the link between them especially in the brain. It is critical to understand the role that autophagy plays in phagocytic process in order to promote the clearance of endogenous and exogenous detrimental materials. In this review, we highlight the studies focusing on phagocytosis and autophagy occurring in the brain and summarizing the possible regulatory roles of autophagy in the process of phagocytosis. Balancing the roles of autophagy and phagocytosis may be a promising therapeutic strategy for the treatment of some neurological diseases in the future.

Acetylcholine in the brain promotes arousal and facilitates cognitive functions. Cholinergic neurons in the mesopontine brainstem and basal forebrain are important for activation of the cerebral cortex, which is characterized by the suppression of irregular slow waves, an increase in gamma (30- 100 Hz) activity in the electroencephalogram, and the appearance of a hippocampal theta rhythm. During general anesthesia, a decrease in acetylcholine release and cholinergic functions contribute to the desired outcomes of general anesthesia, such as amnesia, loss of awareness and consciousness, and immobility. Animal experiments indicate that inactivation, lesion, or genetic ablation of cholinergic neurons in the basal forebrain potentiated the effects of inhalational and injectable anesthetics, including isoflurane, halothane, propofol, pentobarbital, and in some cases, ketamine. Increased behavioral sensitivity to general anesthesia, faster induction time, and delayed recovery of a loss of righting reflex have been observed in rodents with basal forebrain cholinergic deficits. Cholinergic stimulation in the prefrontal cortex, thalamus, and basal forebrain hastens recovery from general anesthesia. Anticholinesterase accelerates emergence from general anesthesia, but with mixed success, in part depending on the anesthetic used. Cholinergic deficits may contribute to cognitive impairments after anesthesia and operations, which are severe in aged subjects. We propose a cholinergic hypothesis for postoperative cognitive disorder, in line with the cholinergic deficits and cognitive decline in aging and Alzheimer’s disease. The current animal literature suggests that brain cholinergic neurons can regulate the immune and inflammatory response after surgical operation and anesthetic exposure, and anticholinesterase and α7-nicotinic cholinergic agonists can alleviate postoperative inflammatory response and cognitive deficits.

Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to a disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong to the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered.

An inverse correlation between the incidence of cancer and neurodegenerative disease has been observed, with the prevalence of cancer peaking around 60 years of age, then slowly tapering off as neurodegenerative diseases increase in the elderly. Although the diseases rarely occur concurrently, the same genes are differentially expressed between the diseases, with four transcription factors found to be in common for their expression. In the brain, mature astrocytes are the origin of astrocytoma, which make up 58.2% of malignant brain tumors in patients 65 or older, while GFAP+ astrocyte-like neural stem cells from the subventricular zone give rise to glioblastoma and anaplastic astrocytoma, which make up 41.6%. Likewise, in neurodegenerative disease, a decrease in astrocyte density is observed in early disease states, and senescent astrocytes increase. Because astrocytes coordinate synaptic function, astrocyte dysfunction likely contributes to or causes initial synapse loss and cognitive decline seen in neurodegenerative disease. In non-disease states, astrocytes retain their ability to successfully re-enter the cell cycle through adult astrogenesis to maintain the neuroenvironment, and controlled astrocytic proliferation could be an important contributor to neurological function. Disruption to this astrogenic balance could account for the inverse correlation of cell cycle dysregulation resulting in malignant astrocytes and tumorigenesis, and astrocytic senescence and cell death without self-renewal in aging resulting in neurodegenerative disease. The current understanding of the astrocytic roles of the transcription factors that could be the cause of this imbalance will be discussed, as well as possible therapeutic approaches to modulate their expression in the astrocyte.

Multiple sclerosis (MS) is a progressive neuromuscular disorder characterized by demyelination of neurons of the central nervous system (CNS). The pathogenesis of the disorder is described as an autoimmune attack targeting the myelin sheath of nerve cell axons in the CNS. Available treatments only reduce the risk of relapse, prolonging the remissions of neurological symptoms and halt the progression of the disorder. Among the new ways of targeting neurological disorders, including MS, there is modulation of gut microbiota since the link between gut microbiota has been rethought within the term gut-brain axis. Gut microbiota is known to help the body with essential functions such as vitamin production and positive regulation of immune, inflammatory, and metabolic pathways. High consumption of saturated fatty acids, gluten, salt, alcohol, artificial sweeteners, or antibiotics is the responsible factor for causing gut dysbiosis. The latter can lead to dysregulation of immune and inflammatory pathways, which eventually results in leaky gut syndrome, systemic inflammation, autoimmune reactions, and increased susceptibility to infections. In modern medicine, scientists have mostly focused on the modulation of gut microbiota in the development of novel and effective therapeutic strategies for numerous disorders, with probiotics and prebiotics being the most widely studied in this regard. Several pieces of evidence from preclinical and clinical studies have supported the positive impact of probiotic and/or prebiotic intake on gut microbiota and MS. This review aims to link gut dysbiosis with the development/progression of MS, and the potential of modulation of gut microbiota in the therapeutics of the disease.

According to the World Health Organization, Traumatic brain injury (TBI) is the major cause of death and disability and will surpass the other diseases by the year 2020. Patients who suffer TBI face many difficulties which negatively affect their social and personal life. TBI patients suffer from changes in mood, impulsivity, poor social judgment and memory deficits. Both open and closed head injuries have their own consequences. Open head injury associated problems are specific in nature e.g. loss of motor functions whereas closed head injuries are diffused in nature like poor memory, problems in concentration etc. Brain injury may have a detrimental effect on the biochemical processes responsible for the homeostatic and physiological disturbances in the brain. Although significant research has been done in order to decrease the overall TBI-related mortality, many individuals suffer from a life-long disability. In this article, we have discussed the causes of TBI, its consequence and the pathobiology of secondary injury. We have also tried to discuss the evidence-based strategies which are shown to decline the devastating consequences of TBI.

As one of the most important elements in our body, zinc plays a part in both the pathophysiology of depression and the antidepressant response. Patients suffering from major depression show significantly reduced zinc levels, which are normalized following successful antidepressant treatment. Recent studies have shown the interaction between zinc, GPR39 and neuropeptides, including galanin and neuropeptide Y (NPY). The zinc-sensing receptor GPR39 forms heterotrimers with 5-HT1A and the galanin receptor GalR1 upon their co-expression in mammalian cells. The oligomerization of these heterotrimers is regulated by the zinc concentration, and this may have an influence on depressive-like behavior. The antidepressant-like effect of zinc is linked to elevated levels of brain-derived neurotrophic factor (BDNF) in brain structures associated with emotion, such as the hippocampus and the amygdala. BDNF regulates neuropeptides, including NPY, cholecystokinin (CCK), and substance P or galanin, which are also implicated in mood disorders. This review focuses for the first time on the interaction between zinc, the GPR39 zinc receptor, BDNF and selected neuropeptides in terms of depression in order to determine its possible role in the neuropharmacology of that illness.

Depression, a well-known mental disorder, has global prevalence, affecting nearly 17% of the population. Due to various limitations of the currently available drugs, people have been adopting traditional herbal medicines to alleviate the symptoms of depression. It is notable to mention that natural products, their derivatives, and their analogs are the main sources for new drug candidates of depression. The mechanisms include interplay with γ-aminobutyric acid (GABA) receptors, serotonergic, dopaminergic noradrenergic systems, and elevation of BDNF levels. The focus of this article is to review the role of signalling molecules in depression and highlight the use of plant-derived natural compounds to counter CNS depression.

New psychoactive substances (NPS) constitute a group of psychotropic substances, designed to mimic the effects of traditional substances like cannabis, cocaine, MDMA, khat, which was not regulated by the 1961 United Nations Convention on Narcotics or the 1971 United Nations Convention on Psychotropic Substances. Illegal laboratories responsible for their production regularly developed new substances and placed them on the market to replace the ones that have been banned; for this reason, during the last decade this class of substances has represented a great challenge for the public health and forensic toxicologists. The spectrum of side effects caused by the intake of these drugs of abuse is very wide since they act on different systems with various mechanisms of action. To date most studies have focused on the neurotoxic effects, very few works focus on cardiotoxicity. Specifically, both synthetic cannabinoids and synthetic cathinones appear to be involved in different cardiac events, including myocardial infarction and sudden cardiac death due to fatal arrhythmias. Synthetic cannabinoids and cathinones cardiotoxicity are mainly mediated through activation of the CB1 receptor present on cardiomyocyte and involved with reactive oxygen species production, ATP depletion and cell death. Concerns with the adrenergic over-stimulation induced by this class of substances and increasing oxidative stress are mainly reported. In this systematic review we aim to summarize the data from all the works analyzing the possible mechanisms through which synthetic cannabinoids and synthetic cathinones damage the myocardial tissue.

Food craving is a health issue for a considerable proportion of the general population. Medications have been introduced to alleviate the craving or reduce the appetite via a neuropharmacological approach. However, the underlying cerebral processing of the medications was largely unknown. This study aimed to meta-analyze existing neuroimaging findings. PubMed, Web of Science, and Scopus were searched to identify relevant publications. Original studies that reported brain imaging findings using functional magnetic resonance imaging (fMRI) were initially included. The reported coordinates of brain activation available from the studies were extracted and metaanalyzed with the activation likelihood estimation (ALE) approach via the software GingerALE. The overall analysis pooling data from 24 studies showed that the right claustrum and insula were the targeted sites of altered cerebral processing of food cues by the medications. Subgroup analysis pooling data from 11 studies showed that these sites had reduced activity levels under medications compared to placebo. The location of this significant cluster partially overlapped with that attributable to affective value processing of food cues in a prior meta-analysis. No brain regions were found to have increased activity levels by medications. These neural correlates may help explain the physiological effect of food consumption by anti-appetite and anti-obesity medications.