Frontiers in Clinical Drug Research - CNS and Neurological Disorders

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterized by the degeneration of motor neurons (MNs) in the spinal cord resulting in progressive muscle atrophy and weakness. Due to its early onset and severity of symptoms, SMA is notable in the health care community as one of the most common causes of early infant death. SMA is caused by missing a functional survival motor neuron 1 (SMN1) gene in patients who produce deficient levels of survival motor neuron (SMN) protein from a copy gene (SMN2), but that could not sustain the survival of spinal cord MNs. Before the end of 2016, there was no cure for SMA, and management only consisted of supportive care. Since then, several therapeutic strategies to increase SMN protein have developed and are currently in various stages of clinical trials. The SMN2-directed antisense oligonucleotide (ASO) therapy was first approved by the FDA in December 2017. Subsequently, in May 2019, gene therapy using an adeno-associated viral vector to deliver the DNA sequence of SMN protein was also approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs, and thereby improve motor function and survival. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a single therapeutic modality may not be sufficient. Neither therapy currently available provides a complete cure. Several other treatment strategies are currently under investigation. These include: establishing an early diagnosis to enable early treatment, a combination of the different treatment regimens, and frequency, dosage, and route variations of drug delivery. Understanding the underlying mechanisms of these treatments is the other area of needed study.

Obesity is a serious health problem, especially in developed countries and poses an increasing danger. It is an important risk factor for some serious and chronic diseases, including hypertension, type II diabetes mellitus, coronary artery disease, stroke, and cancer. Obesity not only causes physical harm to patients but also leads to some common problems, such as low self-esteem, impaired psychosocial functioning, and low activity. Drug-induced weight gain and obesity may harm the patient instead of benefit. Treatment-induced weight gain is one of the important reasons for nonadherence to treatment. In particular, weight gain during adolescence is considered as an “unacceptable side effect” of drugs and causes drug discontinuation. Many drugs (antiepileptics, antidepressants, antipsychotics, etc.) used for the treatment of various neurological disorders are associated with weight gain. On the other hand, few drugs are associated with weight loss. In this chapter, the relationship between the drugs used in the treatment of various neurological disorders and weight change will be discussed.

The nervous system has a very good defence mechanism. The brain is protected by the skull, the spinal cord is shielded by vertebrae and thin membranes. The brain and spinal cord are buffered by cerebro-spinal fluid (CSF). The nervous system is susceptible to assorted disorders. It can be damaged by the structural defects, autoimmune disorders, infection, degeneration disorders, trauma, blood flow interference or tumors. At present, there is no treatment that can alleviate the disorders of the nervous system completely. In recent years, progress has been made in treating nervous system disorders symptomatically but still new product development is lagging behind in treating the disorders originating in the nervous system. This is due to several factors, including the intricacy of a particular disease or efficacy of the drug or delivering system to cross the blood-brain barrier (BBB). This chapter examines the modern state of major nervous system disorders like infection (meningitis), functional disorders (epilepsy, neuralgia), structural disorders (Bell’s palsy, Guillain-Barre syndrome) and degeneration disorder (Huntington disease). The discussion topics include analysis of biological machinery underlying each disease, cytokine expression involved in each disease and how it is regulated in particular disease along with its involvement in targeted therapy, approved pharmaceutical drugs and the development of new therapeutic technologies or customized approaches for drug delivery to particular target (epigenetics, Gene therapy, stem cell therapy). We suppose that with the intensification of modern science, the mobility of nervous system disorders will decline.

Schizophrenia is a thought disorder characterized by hallucinations, delusions, and disorganized thinking. It affects 1% of the world population. Neuroleptics are the drugs used in the treatment of schizophrenia. Besides extrapyramidal side effects, hyperprolactinemia is a major side effect with neuroleptics like haloperidol, risperidone, etc. Hyperprolactinemia results in gynecomastia (male), galactorrhoea, oligomenorrhoea, and amenorrhoea (female) which leads to sexual dysfunction and infertility. Dopamine receptor agonists like cabergoline, bromocriptine, etc are used in the treatment of hyperprolactinemia. However, these drugs may aggravate the symptoms of schizophrenia. So, there is a need for the discovery of drugs that can be used against neuroleptic drug-induced hyperprolactinemia. Lack of suitable animal models for the evaluation of new drugs against neuroleptic drug-induced hyperprolactinemia is a major concern. In this chapter, reviews on neuroleptic drug-induced hyperprolactinemia and the available animal models for the screening of hyperprolactinemia are included.

Glioma is one of the most frequently observed and aggressive brain tumors. Glioma forms 50-60% of brain tumors including astrocytoma, oligodendroglioma, and glioblastoma. Although the integrity of the blood-brain barrier (BBB) is destroyed somehow in glioblastoma (high-grade glioma) patients, similar to many central nervous system diseases, the main anatomical obstacle remains BBB in effective diagnosis, imaging, and therapy.

The survival rate of glioblastoma patients is very low. Early and accurate diagnosis of glioma is essential for therapy chance. When compared with other techniques, noninvasive medical imaging methods provide high specificity and sensitivity. Although MRI is one of the most commonly used modalities in glioma diagnosis and imaging, it possesses limited differentiation in tumor recurrence and pseudoprogression after radiotherapy and combined chemotherapy. Improved MRI techniques can exhibit higher potential in evaluating the pathological features and grading of gliomas before treatment. As a novel method, molecular imaging techniques such as PET/CT can detect genetic mechanisms and related molecular and metabolic differentiation for accurate diagnosis of diseases.

18F-FDG, one of the most commonly used PET radiopharmaceuticals, is highly accumulated in the cerebral cortex. Therefore, 18F-FDG is a non-specific agent in glioma diagnosis and imaging. Non-specific radiopharmaceuticals are not sufficient depending on low sensitivity and specificity in early diagnosis and imaging of proliferation index of tumor cells, the place of hypoxic focuses, tumor load, differentiation of tumor/necrosis, and tumor/inflammation and therapy monitoring of glioma. Therefore, target-specific radiocontrast/contrast agents have been searched for accurate diagnosis, imaging, and therapy monitoring of glioma. Specific PET agents provide differentiation of tumor, necrosis, or inflammation. More specific glioma imaging agents including novel specific Gd or SPIO comprising MRI contrast agents, amino acid tracers like 18F-FET, and peptide tracers like αvβ3 integrin specific 68Ga- RGD and radiolabeled, targeted drug delivery systems have been searched for accurate and early diagnosis of all stages of glioma.