Frontiers in CNS Drug Discovery

An array of molecular underpinnings that dictate brain tumor growth and progression have been unraveled over the past decades. However, brain tumors’ resistance to therapeutics remains a basic challenge, and patients with brain tumors still face a dismal prognosis despite an application of extensive surgery, radiotherapy and chemotherapy. Resistance mechanisms of brain tumors to chemotherapy drugs and other kinds of therapeutic molecules range from the failure of drugs to reach their intended sites due to physiological and pathological obstacles through to the molecular circuitry of the cells which can be easily manipulated by cancer cells themselves. Recent advances and knowledge in sequencing technologies of the human genome have made it possible to perform high throughput screening of compounds libraries against biological targets, shedding light on potential new approaches to treat brain tumors. In this chapter, we describe the molecular characteristics of brain tumors which will explain how cancers cleverly resist chemotherapeutics and molecularly targeted therapies, especially focusing on the most common and lethal brain tumor in human, glioblastoma. We then introduce many promising approaches with the preclinical and clinical developments in brain tumor treatments to overcome, circumvent, disrupt or manipulate the physiological and pathological barriers of brain tumors. We lastly depict the emerging new strategies to facilitate the drug discovery through genome, epigenome, transcriptome and proteome approaches, raising new challenges and identifying new leads in brain tumor therapeutics.

Proteases are involved in different neurodegenerative and neuromuscular disorders. The role of protease inhibitors as therapeutic agents has been the matter of intense research. Given the role of proteases in these diseases, it is appealing to develop a single agent as a “magic bullet” that would target all the disease states. Calpain inhibitors have been tested with success in animal models of human diseases. In this review, we summarize the role of calpain in selected neurodegenerative and neuromuscular diseases. We describe the various instances in which calpain has been implicated and discuss the results of calpain inhibition in each disease entity as well as how targeted calpain inhibition could be beneficial. The focus of this review is to highlight the potential role of targeted inhibition as a therapeutic option and to introduce three newer calpain inhibitors with unique characteristics.

Neurodegenerative disorders are elucidated as genetic and intermittent diseases which are described by progressive nervous system dysfunctions. These disorders have often being correlated with the degeneration of nerve cells. Most prevalent diseases are Alzheimer’s disease (AD) and related dementias, Encephalitis, Epilepsy, Parkinson’s disease (PD), Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington’s disease, Schizophrenia and Prion diseases. All neurodegenerative diseases are disastrous and impact social as well as economic wellbeing. However, the majority of neuropatients are affected by AD, PD and together they cost the health care system almost billions of dollars per year. Besides, Schizophrenia is a severe mystery with no effective medical treatment. Therefore, AD, PD and Schizophrenia have been discussed at length in the present chapter. The AD is characterized by two neuropathological lesions, senile plaques composed of Aβ peptide and neurofibrillary tangles (NFTs) containing aggregated hyperphosphorylated Tau protein. The importance of Tau dysfunction in neurodegeneration is further supported by the enrichment of Tau genetic variants in cohorts of patients suffering from frontotemporal lobar degeneration disorder (FTLD). Memory loss, trouble sleeping, language problems, thinking and reasoning skills are the most common symptoms of AD. The PD is the second most common neurodegenerative disease which involves the breakdown and death of neurons in the brain. The core symptoms of PD are tremor, rigidity, bradykinesia and balance difficulties. Schizophrenia is a genetic brain disorder. Delusions, hallucinations, social withdrawal and disturbed thinking are some of its key symptoms. The genes causing these neurodegenerative disorders have been identified for more than two decades. Key researchers in this field have revealed numerous events at molecular and cellular levels, thus playing an important role in these fatal disorders. Many associated pathological events and therapeutic correlations are not clearly understood and therefore, there is no known cure for these chronic and progressive neurological disorders. This chapter aims to address AD, PD and Schizophrenia researches that may divulge novel mechanisms and targets for therapeutic intervention. It collates the significant findings of various experts in studying these degenerative diseases and stimulates novel perception to the campaign against devastating neurodegenerative diseases.

Chronic pain, differently from nociceptive pain, results from a maladaptive response of the body. Accumulating evidence shows that the mechanism of persistent pathological pain is mediated by complex interactions between sensory neurons and glial cells, namely astrocytes, microglia, and oligodendrocytes. In this chapter, we focus on the current understanding of the neuroimmune contribution to pathological pain and the mechanisms by which glial cells interact with sensory neurons to modulate pain and inflammation. The glial cells biology and how sensory neurons can modulate inflammatory response are also highlighted topics in this chapter. Given the heterogeneous immune functions of different cells in the spinal cord and the sex differential role of glial cells in chronic pain, we also explore how this could be harnessed to develop new therapeutic approaches for pain relief.

Inhibitors of the acetylcholinesterase enzyme were first described in the latter part of the 19^th century. Some of these inhibitors also inhibit the butyrylcholinesterase enzyme. Therapeutic uses of the cholinesterase inhibitors include ophthalmology, anesthesia, myasthenia gravis, muscarinic antagonist overdose and Alzheimer’s disease. Many pesticides act by inhibiting cholinesterase, with the potential for accidental or deliberate poisoning. Cholinesterase inhibitors were also developed as nerve agents for chemical warfare. This chapter describes the discovery and early studies on the effects and mechanism of action of cholinesterase inhibitors. Subsequent development led to the discovery of a large and varied group of cholinesterase inhibitors. These drugs will be discussed with regard to their therapeutic uses and clinical considerations. Finally, concerns regarding cholinesterase inhibitor toxicity when used as pesticides and nerve agents will be discussed.