The prevalence of neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple sclerosis (MS) are growing in the world, but their pathogenesis is unclear and effective treatment does not exist. Neuroinflammation is associated with many neurodegenerative mechanisms involved in neurodegenerative diseases. The human gut microbiota is an aggregate of microorganisms that live in the gastrointestinal tract (GIT) that plays a crucial role in maintaining human health and the pathogenesis disease condition. The microbiota can affect neuronal function through neurotransmitters, vitamins, and neuroactive microbial metabolites like shortchain fatty acids. The change in gut microbiota architecture causes increased permeability of the intestine and immune system activation, contributing to systemic inflammation, neurological injury, and eventually neurodegeneration. Available data suggest that the microbiota send signals to the central nervous system (CNS) by activating afferent neurons of the vagus nerve via neuroendocrine and neuroimmune pathways. The molecular interaction between the gut/microbiome and CNS is complex and bidirectional, ensuring gut homeostasis and proper digestion. Evidence suggests that dysfunction of the gut-brain axis could be a significant factor leading to many disorders of CNS. In this chapter, we explore how the gut microbiome may affect brain function and the development of neurological disorders. In addition, we are also trying to highlight the recent advances in improving neurological disease by supplemental probiotics and faecal microbiota transplantation via the concept of the gut-brain axis to combat brain-related dysfunction.
Pediatric tumors of the central nervous system (CNS) are the second most common type of solid childhood cancer. As such, they have a major effect on the rates of morbidity and mortality in children. CNS tumors originate from abnormal cells in the brain and/or spinal cord, which can be classified as either benign or malignant. They can be further subdivided into different categories based on several principal aspects, such as tumor location, histopathology, and developmental age. Among these various characteristics, age is one of the most consequential determinants for CNS tumors. Specific groups between 0 and 21 years of age, for instance, have radically divergent landscapes in terms of their tumor incidence and unique biology. Depending on the age of the child, key case features may differ like the clinical evaluation, medical diagnosis and prognosis, recommended therapy and treatment courses, anticipated responses and tolerability to treatment, and management of side effects. Effective teamwork is another crucial component for the successful management of pediatric CNS tumors. In patient-and-family-centered care, ensuring a detailed education of the children and their families, as well as their involvement in the decision-making process where appropriate, is imperative. To determine the best available options for the patient, multidisciplinary medical teams will often deliberate over all of the possible procedures. The holistic care provided by these interprofessional collaborations for this vulnerable population will depend on the age of the child, in addition to the level of patient and family participation. Evidence shows that support and counseling of the patient and their family during the entire treatment process can have a significant impact on outcomes. This chapter will review the essential diagnostic and prognostic considerations of childhood CNS tumors, with special emphasis placed on favorable therapies and treatments, including in-depth discussions around the multi-faceted responses to treatment and the management of its side effects. In particular, this content will highlight the critical role that age, and interdisciplinary healthcare teams play in comprehensive disease management.
Affecting more than 50 million people worldwide and with high global costs annually, neurological disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD) are a growing challenge all over the world. Globally, only in 2018, AD costs reached an astonishing $ 1 trillion and, since the annual costs of AD are rapidly increasing, the projections estimate that these numbers will double by 2030. Considering the industrial perspective, the costs related to the development of new drugs are extremely high when compared to the expected financial return. One of the aggravating factors is the exorbitant values for the synthesis of chemical compounds, hindering the process of searching for new drug candidates. In the last 10-year period, an average of 20 to 40 new drugs were approved per year, representing a success rate of less than 6%. However, the number of referrals for new drug orders and/or applications remained at approximately 700 each year, reinforcing the difficulty in the process of identifying and developing novel drugs. Regarding neurodegenerative diseases, the FDA (USA) approved 53 new therapies in 2019, including 48 new molecules and, from these, three are medicines and two are vaccines. The main drugs recommended for the treatment of these disorders are included in the following classes: Dopamine supplement (Levodopa), Monoamine oxidase (MAO) inhibitor (Selegiline, Rasagiline), Dopamine agonist (Apomorphine, Pramipexole), and Acetylcholinesterase inhibitor (Donepezil, Rivastigmine, Galantamine). Additionally, the current pharmacological treatments are not able to cure these patients and considering the etiological complexity and the prevalence of neurological disorders, scientists have a great challenge in exploring new therapies and new molecules to find an adequate and viable treatment for these diseases. Clinical trials are essential in this process and thus, this chapter describes the most important drugs that were targets of phase III and IV clinical studies in the last five years, associated with the most common neurological disorders worldwide, AD and PD. Information about mechanisms of action, experimental studies in other diseases that support their use, and chemical structure of the drugs are included in this chapter. Additionally, nature as a source of valuable chemical entities for PD and AD therapeutics was also revised, as well as future advances in the field regarding tracking new drugs to get successful results and critical opinions in the research and clinical investigation.
Central Nervous System (CNS) disorders are a massive burden on the global health system, including a broad range of clinical conditions, such as epilepsies, depression, dementia, multiple sclerosis, and Parkinson’s disease. Permanent efforts are being made to find early, non-invasive, and effective diagnostic methods, as well as efficient and safe drug-based treatments for CNS conditions. Nevertheless, many patients displaying these clinical conditions still face the lack of an effective pharmacotherapy to cure the diseases or at least to properly control the progression of symptoms. Currently, epilepsies present an estimated prevalence of 0.5%–1% worldwide, and around 30% of the patients remain refractory to the available drug treatment. The comorbidities that affect epileptic patients, such as cognitive impairment and depression, are major public health challenges. This scenario highlights the urgent need for approving new therapeutic tools for CNS diseases. A successful development process of a new compound presenting therapeutic potential can range up to 20 years and cost hundreds of millions of US dollars, from the initial characterization of the in vitro chemical and biological properties until clinical trials. Additionally, drug development has a low success rate in the case of CNS conditions. In this context, drug repurposing (or drug repositioning, DR) is an alternative way to reduce the cost and accelerate the process of a drug-based treatment approach since it identifies a novel clinical application for an existing compound already approved for a distinct indication. In the present chapter, we aim to describe recent outcomes of DR aiming at CNS pathological conditions, especially discussing the recent clinical trials and their impacts on future endeavors in the search for the management of epilepsies and related comorbidities.
Placebo is defined as the therapeutic response to inert treatment. However, this is a bit simplistic because comprehending the biological basis of the placebo effect requires understanding the entire therapeutic context and the patient immersed in it. Placebo does not cure the disease but alleviates symptoms. The placebo impact must be seen in the context of the recipients’ cultural milieu, psychosocial background, the tone and tenor of the accompanying verbal communication (caring, indifferent, unfriendly), therapeutic rituals (e.g., tablet, injection, or a procedure, including diagnostic tests), symbols (white coat, syringe, the diagnostic paraphernalia), and its meanings to the patient (past experiences and personal hope). Placebo is the inert treatment juxtaposed against the broad context of the accompanying sensory and sociocultural inputs that signal benefit. It could also be the harm in the case of nocebo. A major objective of a standard clinical trial is to eliminate or at least minimise the influence of placebo. Many methods have been devised to measure and eliminate placebo responders in the trial populations. The neurological basis of the placebo effect is complex and must have an evolutionary basis because the susceptibility to placebos may be traced back to animals and birds. The placebo effect probably owes its evolutionary origin to signalling sickness and the ability to draw comfort from winning sympathetic attention and care from conspecifics. Pain being a complex sensory experience with a strong affective component, the neuronal pathways that reflect both sensory experience and the affective components have been explored in the study of the placebo effect. Placebo research, having expanded from psychology to neurology, presently involves research tools that include pharmacology, brain imaging, genetics, animal models, etc. This review will discuss multiple dimensions of the placebo effect, including evolutionary, cultural, psychosocial, and neurological aspects, in addition to providing cues for transformational implications in clinical trials and therapeutic modalities that benefit society. Contemporary medicine is demonising placebo because it is a confounder in clinical trials. It would be much more useful if the healthcare system can harness the therapeutic potential of the placebo effect by manipulating the therapeutic context.
Nowadays, organophosphorus poisoning is the most common emergency throughout the world. Two functionally different types of drugs are used in common to treat such intoxication cases. The first type includes the reactivators of acetylcholinesterase (AChE)-oximes, which have the capability to restore the physiological function of inhibited AChE. The second type includes anticholinergic, such as atropine that antagonizes the effects of excessive ACh by blocking muscarinic receptors. Alternatively, anticholinergic and reactivators may be co-administered to get synergistic effects. At muscarinic and nicotinic synapses, organophosphorus compounds inhibit AChE release by phosphoryl group deposition at the enzyme's active site very quickly. AChE regenerative process can be accelerated by detaching the OP compound at -OH group of the enzyme. OP compound combines with the AChE enzyme forming a complex and making it inactive. After ageing of the inactive state of AChE, it is difficult to break the complex to regenerate the enzyme resulting in acetylcholine accumulation at synapses. To counter the effect of OP compound, oximes catalyse the reactivation of active AChE by exerting nucleophilic attack on the phosphoryl group. Oximes theoretically remove OP compound from the complex by acting on phosphoryl bond resulting in enzyme reactivation. Reactivation of AChE inhibited by OP compounds through the above mentioned approach poses certain limitations. There is no universal antidote capable of effectively restoring AChE inhibited by wide-ranging OP compounds. The oxime reactivators are efficient only when administered before the “ageing” of AChE-OP complex. Anticholinergic drugs, like atropine, are effective only on muscarinic receptors but not on nicotinic receptors (nAChRs).
Neurodegenerative disorders are considered major global health problems associated with nervous system dysfunction, progressive neuronal cell loss with aging, and several pathological and sporadic factors. Parkinson’s disease, Alzheimer’s disease, Prion disease, Huntington’s disease, and multiple sclerosis are the main neurodegenerative diseases that raise significant concern among health scientists. The etiology of different neurodegenerative diseases is different, and they majorly affect the nervous system, including the brain, spinal cord, and peripheral nervous system. Neurodegenerative diseases are linked with motor dysfunction, anxiety, memory loss, depression, cognitive impairments, etc. These diseases can be hereditary or caused by toxicity, metabolic disorders, or pathological changes in the brain. Therefore, interest has been growing in the development of different neuroprotective agents of natural origin that could work effectively against these diseases. In that aspect, phytochemicals have shown high potential with minimal side effects in various in vitro and in vivo studies. Cinnamic acids with phenylpropenoic moiety are abundant in many natural resources. These are available in many forms, such as ferulic acid, caffeic acid, etc. They also have a variety of pharmacological properties, including anti-inflammatory, anti-oxidant, anti-amyloid, and neuroprotective properties. This chapter summarizes the role of naturally occurring cinnamic acids and their derivatives to develop the mechanistic aspects of neuroprotective therapeutics in neurodegenerative diseases. Future challenges are also discussed to provide beneficial information and therapeutic strategies.
Neurodegenerative disorders are considered major global health problems associated with nervous system dysfunction, progressive neuronal cell loss with aging, and several pathological and sporadic factors. Parkinson’s disease, Alzheimer’s disease, Prion disease, Huntington’s disease, and multiple sclerosis are the main neurodegenerative diseases that raise significant concern among health scientists. The etiology of different neurodegenerative diseases is different, and they majorly affect the nervous system, including the brain, spinal cord, and peripheral nervous system. Neurodegenerative diseases are linked with motor dysfunction, anxiety, memory loss, depression, cognitive impairments, etc. These diseases can be hereditary or caused by toxicity, metabolic disorders, or pathological changes in the brain. Therefore, interest has been growing in the development of different neuroprotective agents of natural origin that could work effectively against these diseases. In that aspect, phytochemicals have shown high potential with minimal side effects in various in vitro and in vivo studies. Cinnamic acids with phenylpropenoic moiety are abundant in many natural resources. These are available in many forms, such as ferulic acid, caffeic acid, etc. They also have a variety of pharmacological properties, including anti-inflammatory, anti-oxidant, anti-amyloid, and neuroprotective properties. This chapter summarizes the role of naturally occurring cinnamic acids and their derivatives to develop the mechanistic aspects of neuroprotective therapeutics in neurodegenerative diseases. Future challenges are also discussed to provide beneficial information and therapeutic strategies.<br>
Alzheimer’s disease is known to be the most common cause of dementia with increasing number of people suffering every year. In healthy adults, there are millions of neurons in the brain. Degeneration starts and extends in Alzheimer's disease many years before the initial symptoms show up. The neurons taking part in cognitive functions destroy gradually leading to functional disability and finally to death. β amyloid plaques and tau protein are known as the most responsible causes of Alzheimer’s disease resulting in neurodegeneration. Inflammation, atrophy and dysfunction in glucose metabolism will follow. The three stages of the disease include mild, moderate and severe. The patient will have difficulty in cognitive functions, show changes in behavior and will need care for everyday needs, which increases by the disease progress. There are pharmacologic and non-pharmacologic approaches for treatment. The pharmacologic approaches comprise acetylcholinesterase (AChE) inhibitors such as donepezil or N-methyl-d-aspartate (NMDA) receptor blockers like memantine. None of them stops the disease but alleviate the symptoms. On the other hand, non-pharmacologic approaches are usually used to improve the patient’s quality of life or improve the behavioral aspects of the disease. Recently, involving physical activity as a non-pharmacologic method of treatment for Alzheimer’s disease has been the focus of many studies. This chapter will have a glance at the clinical trials that were conducted regarding the effect of physical exercise and its impact on Alzheimer’s disease.
Alzheimer’s disease (AD) is a progressive neurological disorder. Recent studies show that AD is the most common cause of dementia. There are several symptomatic treatments available to counterbalance the neurotransmitter disturbance. Currently, cholinesterase inhibitors are available for the treatment of mild to moderate AD. In addition to that, memantine (an N-methyl-D-aspartate receptor non-competitive antagonist) is also available for moderate to severe AD. Poor blood-brain barrier permeability is a limitation of existing drugs. These drugs may slow the disease progression, but there are chances of reoccurrence of the disease. Several medicinal plants such as Jasminum sambac, Rosmarinus officinalis, Eucalyptus globulus, Nigella sativa, and Acorus gramineus are reported to have neuroprotective effects. Salvia officinalis has cholinergic binding properties. Ginger root extract may prevent behavioral dysfunction in AD. Extensive research on these plants should be carried out. Drug delivery systems such as lipid nanoparticles, polymer nanoparticles, nano-micelles, nano-gels, liposomes, phytosomes, etc., could significantly improve the pharmacokinetics, stability, efficacy and reduce the side effects. Phytosomes have the advantage over other drug delivery systems to selectively target the drugs into the brain. In contrast to traditional approaches, polar phytoconstituents loaded phytosomes are more bioavailable on the site of brain tissue, as they can easily go for systemic circulation crossing the Blood-Brain Barrier (BBB). Phytosomes have a low hazard profile as toxicological outcomes are negligible and assure duration of action at a low-risk profile due to upgraded absorption of the active constituents. In addition to this, the improved pharmacodynamic properties of phytosomes make them suitable for the treatment of neurological disorders.
Behavioral and substance addictions share more similarities than differences in etiological, phenomenological, and clinical presentations. Interactions between the variables of predisposing (i.e., neurobiological and psychological constitutions) and moderating (i.e., coping style and cognitive and attentional biases), as well as variables of mediating (i.e., affective and cognitive reactions to situational triggers) in combination with reduced inhibitory control may accelerate or reduce the developing of specific versions of model for addictive behaviors. Around 50% individuals’ variability in becoming addicted to substance (nicotine, alcohol, or illicit drugs) is attributable to genetic factors. Genetic variations to addiction susceptibility and environmental factors such as stress or social defeat also alter brain-reward mechanisms impart vulnerability to addiction. The emergence and maintenance of addiction might be the consequences of chronic exposure to drugs remodeling the chromatin structure including FosB, Cdk5, G9a, and BDNF around genes. Only few drugs for substance use disorders (SUDs) are approved by the FDA, But QSP approaches provide valuable strategies for designing novel prevention or treatment towards drug addiction. Conjugate vaccines and monoclonal antibodies treatments generating high-affinity anti-drug IgG antibodies neutralizing drug doses in the serum might lead the immunotherapy for SUDs in the future.
The rapid increase in the incidence of dementia has enormous socioeconomic impacts and costs for governmental health systems all over the world. Despite this, finding an effective treatment for the different types of neurodegenerative diseases (NDs) so far represents a challenge for science. The biggest obstacles related to NDs are their multifactorial complexity and the lack of knowledge of the different pathophysiological pathways involved in the development of each disorder. The latest advances in science, especially those related to the systems biology concepts, have given new insights for a better comprehension of such multifactorial networks related to the onset and progression of NDs, and how Medicinal Chemists could act in the search for novel disease-modifying drug candidates capable of addressing the multiple pathological factors involved in neurodegeneration. The multi-target directed ligands (MTDLs) concept has captivated and opened new windows for the creativity and rationality of researchers worldwide in seeking innovative drug candidates capable of modulating different molecular targets by a single multifunctional molecule. In fact, in the last two decades, thousands of research groups have dedicated their efforts to the use of molecular hybridization as the main tool for the rational design of novel molecular scaffolds capable of expressing multi-target biological activity. In this way, this chapter addresses the most recent pathophysiological hallmarks of the most high-impact NDs, represented by Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis, as well as the state-of-art in the design of new MTDLs, inspired mostly by natural products with improved druggability properties.
Conditions caused by the lesion and progressive death of neuronal cells inthe organism include neurodegenerative disorders and neuropathic pain. They representthe major causes of disability in Western countries. These conditions are more commonin elderly people, and their prevalence, therefore, is expected to grow in the futurebecause of the aging population. Currently, curative therapies againstneurodegenerative disorders and neuropathic pain are not available. Existing treatmentsmay provide temporary symptomatic relief to some patients but fail to stop neuronaldegeneration, protect and restore damaged neurons. Neurotrophic factors are smallsecretory proteins whose main function is to support the survival of neurons. Therefore,they hold considerable promise for disease-modifying treatment of neurodegenerativedisorders and neuropathic pain. However, despite promising results in preclinicalstudies, clinical translation of neurotrophic factors has so far achieved limited success.Neurotrophic factors are different from traditional chemical compounds used as drugsin the majority of cases, and this complicates their clinical use. Biology of neurotrophicfactors and their absorption, distribution, metabolism, excretion, and pharmacokineticsproperties dictate special requirements to clinical trials design. Patients taking part inclinical trials, delivery system, delivery paradigm, and the dose of neurotrophic factorshould be carefully considered in trial design in order to ensure that the treatment willimprove the condition of patients.In the present chapter, the author summarizes the available literature regardingsignaling of neurotrophic factors, provides the data about their preclinical evaluation inanimal models of neurodegenerative disorders and neuropathic pain, describes theresults of clinical trials conducted with neurotrophic factors in patients, and discussesthe limitations of these trials and translational problems faced by researchers andclinicians in this field. The author will further discuss emerging alternatives toneurotrophic factor proteins with improved translational perspectives, such as mutantproteins, small molecules, and peptides targeting the receptors of neurotrophic factors.The author will review attempts of clinical translation of glial cell line-derivedneurotrophic factor family ligands for the treatment of Parkinson’s disease andneuropathic pain. The author will briefly describe the non-conventional cerebraldopamine neurotrophic factor tested in Phase I/II clinical trial in patients withParkinson’s disease. The author will also describe the data concerning the clinical evaluationof other neurotrophic factors in the above-mentioned conditions.
Neurodegenerative diseases such as Parkinson's, Alzheimer’s, Huntington’s etc. have their root in damaged nerve cells followed by the loss of their functions. Though the exact reason for different neurodegenerative diseases is still unknown, degradation and accumulation of proteins in neurons, oxidative stress, inflammation, defects in mitochondria, genetic mutation etc., are said to be the general factors that leads to this disease. The old ages are the worst affected group due to the rise in human life expectancies. Although there is no complete cure for this disease, some drug treatments have been found to be useful for reducing few of the physical or mental symptoms associated with neurodegenerative diseases. In fact, most neurodegenerative disorders show multiple symptoms;a promising result can be achieved only through the combination of different compounds like natural plant extracts which have many disease targets. Antioxidants are proven to have the capacity to act against the oxidative stress developed in the cells. So, antioxidant rich plant extracts can be utilized for the treatment of neurological related disorders. Several studies are being carried out on the effect of various plant extracts on the neurodegenerative disease prevention, management as well as treatment. This chapter will discuss the in vitro, in vivo and clinical studies conducted on the effect of various plant extracts for the treatment and prevention of different neurodegenerative disease conditions.
<div>Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental</div><div>disorder characterized by hyperactivity, impulsivity, and inattention and affects</div><div>between 2 and 9% of school-aged children.<br><br></div><div>Accumulating evidence indicates that ADHD is caused due to imbalances of the</div><div>dopamine (DA) and noradrenaline (NA) systems and provides support for the</div><div>recommendation of medications such as methylphenidate (MPH) and atomoxetine</div><div>(ATX), which work on each system, respectively. MPH inhibits the reuptake of</div><div>catecholamines, especially DA, and ATX inhibits the reuptake of NA predominantly in</div><div>the prefrontal cortices to improve ADHD symptoms.<br><br></div><div>There are no objective methods for evaluating the effects of medications. Clinicians</div><div>usually refer to the severity levels of symptoms listed on rating questionnaires for</div><div>subjective measures of ADHD symptoms conducted by children’s parents or teachers.</div><div>Therefore, more objective approaches are urgently required.<br><br></div><div>The use of non-invasive functional neuroimaging modalities has been reported as a</div><div>method for visualizing neural function, and such modalities include functional</div><div>magnetic resonance imaging (fMRI), positron emission tomography (PET),</div><div>magnetoencephalography (MEG), and, lately, functional near-infrared spectroscopy</div><div>(fNIRS). Since the 2000s, fMRI research has revealed pharmacological effects of</div><div>ADHD therapeutic agents in the PFC. However, elimination rates for fMRI</div><div>measurements have been high, especially in pediatric cases. In this regard, fNIRS,</div><div>which measures cortical oxyhemoglobin concentration changes associated with</div><div>neuronal activation, has several advantages, such as its usefulness in accessibility and</div><div>tolerance of body motion.<br><br><div>Our fNIRS-based method with young ADHD children showed the neural dysfunction</div><div>and neurofunctional modulation induced by medication. Hemodynamic responses in</div><div>the right PFC during an inhibition task, a go/no-go task, were robustly lower in ADHD</div><div>children than in controls. These responses could differentiate ADHD from controls</div><div>individually, with a sensitivity of 90% and a specificity of 70%. Regarding</div><div>pharmacological effects, randomized, double-blind, placebo-controlled, crossover</div><div>studies have revealed normalized hemodynamic responses in the right PFC caused by</div><div>MPH and ATX in ADHD children during go/no-go tasks. On the other hand, during an</div><div>attentional task, an oddball task, ATX led to activation in the right inferior parietal</div><div>cortex (IPC) in addition to the PFC, while MPH induced hemodynamic responses only</div><div>in the right PFC. These responses reflect neuropharmacological effects on each of these</div><div>two neural networks. MPH upregulates the dopamine system, and ATX affects the</div><div>noradrenergic system. Furthermore, MPH-induced neuropharmacological effects in</div><div>ADHD children with or without comorbid autism spectrum disorder (ASD) provided</div>evidence for a differing neurofunctional pathology between the two groups.<br><br><div>This evidence provides a promising possibility to enable diagnosing and evaluating</div><div>treatments for ADHD patients at the clinical level.</div></div>
Despite our growing understanding of chronic pain mechanisms, an alarming proportion of patients worldwide remains refractory to treatment. Chronic pain is complex, involving the interaction of both neuronal and non-neuronal systems. Several studies focused on immune, glial and mesenchymal stem cells (MSCs) have recently revealed key roles of these non-neuronal players in the initiation and perpetuation of chronic pain. The complexity of chronic pain is reflected by the difficulty of its therapeutic control, in particular when using mono-target drugs. A good proportion of these drugs target neuronal pathways, and serious concerns arise when it comes to the use of opioids and abuse liability. In contrast, novel pain drugs targeting non-neuronal components of chronic pain are scarce. Exceptions include classical nonsteroidal anti-inflammatory drugs, or those modulating trophic factors, although their use remains restricted to the presence of appropriate targets. Synthetic oligodeoxynucleotides have been used as immune system modulators for the last 15 years. One of them, IMT504, a non-CpG oligodeoxynucleotide, exhibits remarkable, long-lasting anti-allodynic and anti-inflammatory properties upon single-dose systemic administration in rodent models of inflammatory or neuropathic pain. Mounting evidence suggests that the beneficial effects of IMT504 relate to actions on the immune system, glial cells and MSCs. In this state-of-the-art chapter, we address the current knowledge of the role of IMT504 over non-neuronal cells, its impact on chronic pain, and its translational potential. We also propose that further analysis on its mechanisms of action will be key to the identification of novel and effective multi-target pain drugs without abuse liability.
Lithium is a type of psychotropic drug, belonging to the normothymics classification group. It is used in the treatment of affective disorders such as manic and hypomanic phases of bipolar disorder and severe and treatment-resistant depression. It also has anti-suicidal properties and a neuroprotective effect on neurodegenerative diseases. This article presents findings regarding the effects of lithium in experimental pathology of the central nervous system in mice and rats. In clinical practice, lithium is the standard for pharmacological treatment of bipolar disorders. The drug is also effective in treating depression. It suppresses aggressiveness and is a therapeutic agent in the treatment of chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. Lithium salts however can be highly toxic even in relatively low doses. The mechanism of action of lithium salts can be realized through the inhibition of glycogen synthase kinase -3β (GSK-3β) and inositol monophosphatase 1 (IMAP1). Inhibition of GSK-3β is considered to be one of the fundamental mechanisms in the implementation of the action of lithium ions on the body. Lithium stabilizes adenylate cyclase activity and acts as an antagonist of sodium ions in nerve and muscle cells. One of the ways to deliver lithium to target organs is to combine lithium salts with a sorbent (a solid porous carrier). This approach made it possible to create modified sorbents for the prolonged delivery of components such as lithium and silver. A new drug – a complex of lithium citrate and a sorbent – aluminum oxide and polydimethylsiloxane (lithium complex) was created at the Research Institute of Clinical and Experimental Lymphology – a branch of the Institute of Cytology and Genetics SB RAS. Its anxiolytic and adaptogenic effects were observed over the course of preclinical studies. The lithium complex improved cognitive functions in experimental animals, influenced the electrophysiological activity of the brain and had positive effects on the behavior of mice in the experimental model of chronic social stress. The lithium complex is therefore a promising drug for the treatment of neurological and psychoemotional disorders.
