Frontiers in Clinical Drug Research - CNS and Neurological Disorders

Microdialysis sampling has been coupled with several imaging modalities over the past two decades to either support the development of imaging approaches as diagnostic, prognostic or treatment response biomarkers, or to use this temporally rich sampling approach of brain tissue in parallel with one or more imaging modalities to provide an integrated, systems neuropharmacology, perspective of normal and diseased brain physiology. This chapter provides a comprehensive review of the scientific literature that encompasses several imaging modalities (including PET, MRI, EEG, CT) that relied on microdialysis sampling for its supportive and/or parallel use in systems neuropharmacology research. A review of the important role microdialysis has played in supporting several PET imaging applications used in neuropharmacology research is provided. Integrated with PET, various MRI modalities, EEG and CT, microdialysis has deepened understanding of various neurotransmitter systems and their temporal and spatial integration as an in-tune, “normal” or dysynchronous, “diseased” system. Parallel use of microdialysis in humans suffering from traumatic brain injury or chronic epilepsy has been coupled with PET, MRI, EEG and CT approaches to develop systems-level understanding at the cellular, regional, and whole brain levels. Throughout the chapter, several publications are discussed that exemplify the results of this research. The chapter concludes with a presentation of the integrated use of microdialysis with imaging in Alzheimer’s Disease research, ending with the hope for expanded use of imaging modalities that can even be used in an ambulatory capacity, and how microdialysis can continue to play its established role to support their development and use in understanding and treating this disease.

Major depressive disorder (MDD) is the most prevalent mood disorder worldwide and the third leading cause for years lived with disability. Major challenges encountered in the treatment of MDD include high non-responder and relapse rates and delayed therapeutic onset. MDD is a heterogeneous condition, and the identification of more homogenous groups of patients may facilitate the selection of optimal therapeutic strategies. Different approaches have been considered for the subtyping of depression, including etiological factors, clinical symptoms, biological markers, and treatment response. However, the optimal strategy for the identification of more homogenous groups of patients remains elusive. In this chapter, the subdivision of depression into melancholic and atypical subtypes, the significance of considering hypomanic or manic symptoms in the diagnosis and treatment of depression, and the importance of combining biological and clinical findings based on the approach implemented by the Research Domain Criteria (RDoC) project are discussed. Phenotypic associations between atypical depressive symptoms and obesity-related traits have also been identified that may arise from shared pathophysiologic mechanisms. Thus, the development of treatments effectively targeting immunometabolic dysregulations may benefit patients with atypical depression. The presence of hypomanic or manic symptoms in patients with depression may be relevant for the selection of a therapeutic strategy. Notably, the longitudinal course of mood-related symptoms should be considered, and a dimensional approach should be applied to capture the complexity of mood disorders. The application of the RDoC framework to mood-related symptoms allows the use of a transdiagnostic dimensional approach, which incorporates pathophysiological and clinical data and considers the influence of neurodevelopmental and environmental factors. Future studies on MDD subtypes and more broadly defined mood-related symptoms should focus on the identification of biologically relevant disease phenotypes and take into account the role of neurodevelopmental and environmental factors for the identification of new therapeutic targets.

Chimeric antigen receptor (CAR)-T cell therapy has recently been introduced as a promising therapeutic T cell-based therapy. Autologous T cells are collected from the patient, engineered in vitro to express artificial chimeric receptors against a specific tumor antigen, and infused into the patient. The success of adoptive CAR-T cells for cancer immunotherapies, particularly in hematological malignancies, inspired researchers of the field. These armored T cells also showed a great potential to be used in the treatment of pediatric brain tumors and autoimmune diseases. In this chapter, we summarize the basics and developments of CAR-T cells from our previous review articles and then discuss the current progress in the pre-clinical and clinical application of CAR-T cells in brain tumors and autoimmune diseases.

Thyrotropin-releasing hormone (TRH) is a neuropeptide having many biological and pharmacological activities. TRH (protirelin tartrate) has been used for the treatment of persistent disturbance of consciousness disorder because of its amelioratory effect. However, therapeutic use of TRH entails problems, such as its low lipophilicity, short half-life times due to specific degradation enzymes, and low penetration of the blood-brain barrier (BBB) for access to the central nervous system (CNS). To overcome such problems, a large number of TRH mimetics have been developed for the treatment of various neurological and psychiatric disorders, including spinocerebellar degeneration (SCD), cognitive impairment, and Alzheimer’s disease (AD), given by non-oral routes such as intravenous (iv) administration. However, orally effective TRH mimetics are needed to help improve the quality of life (QOL) of patients. As the first orally active TRH mimetic for the treatment of SCD, Taltirelin (Ceredist) has been launched in Japan for administration twice a day. Recently, rovatirelin reported to have high oral bioavailability (BA), was developed for SCD as a potentially effective treatment option in clinical trials by oral administration once a day. This would allow treatment with TRH and its mimetics to be moved from the hospital to outpatient or homecare facilities, and their use for a wider range of disorders. In the near future, TRH and its mimetics should become available as one of the key treatments for various neurological and psychiatric conditions, such as AD, Parkinson’s disease (PD), depression and so on.

Alzheimer’s disease (AD) is characterized by impaired cognitive functions due to irreversible neuronal injury by the formation of abnormal beta-amyloid plaques (aggregated amyloid beta-peptide (AβP)) in the brain. Among various secretase enzymes, beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1) functions in the first step and is the rate-limiting step of the AβP formation. Therefore, BACE1 has attained considerable attention as a novel therapeutic target for the management of AD. Inhibition of BACE1 prevents the generation of amyloid-beta and hence blocks the impending pathological events that occur due to beta peptide accumulation. The drugs being used clinically (acetylcholinesterase inhibitors and NMDA receptor antagonists) so far have not been able to cure AD completely and are associated with a high risk of toxicity. Thus, finding a newer therapeutic regimen for AD is of utmost importance and BACE1 could be a potential target for developing newer drugs.

Plants are described as memory enhancers in various ancient systems of medicines, including Ayurveda and Traditional Chinese System, and thus, are being used by mankind for improving intellect skills and cognition. Recently, research has paid much attention to the drugs of natural origin as these are generally considered safe and devoid of side effects. Therefore, herbal extracts are explored for specific BACE1 inhibitory activity, and compounds (BACE1 inhibitors) are isolated. There are several plant extracts and phytoconstituents that have demonstrated marked BACE1 inhibitor activity along with superior biosafety. This chapter highlights the role of BACE1 in the pathogenesis of memory deficit associated with AD and draws attention to the distinct potential natural BACE1 inhibitors for AD treatment.

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.

Multiple sclerosis (MS) is a well-known chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). It is considered the most common autoimmune demyelinating disease of the CNS. It affects mainly young adult females between 20-40 years of age. MS was previously considered a Tlymphocyte- disease, but now B lymphocytes appeared to have a critical role in MS's pathogenesis. Affected patients showed lower quality of life with an increased death rate than the general population. The treatment of MS is challenging, and many drugs have evolved primarily for the last 20-30 years. Since the introduction of interferons in 1993, there are more than sixteen disease-modifying therapies (DMTs) approved. These drugs have different pharmacologic forms like injections, oral forms, and intravenous infusion drugs. Each one has its benefits and drawbacks. Moreover, like any other patient, MS patient has other symptoms that are not covered by DMT and need symptomatic treatment. In this chapter, we attempt to present medications used to treat acute relapse, different DMTs, symptomatic treatment for different MS symptoms. Besides, we give attention to drugs under clinical trials.