Frontiers in Clinical Drug Research - CNS and Neurological Disorders

Spinal cord injury (SCI) is a devastating event that often leads to profound disability. Traditionally, the treatment for such injury consisted of steroids, spinal decompression and stabilization surgery, and physical therapy. Despite all these treatments, however, prognoses for meaningful functional recovery remained grim. Recently, laboratory-based advancements in our understanding of central nervous system injuries at the cellular and molecular levels have ushered in new drug treatment strategies for neuroprotection and regeneration following SCI. Emerging strategies include pharmacotherapy to reduce spinal cord ischemia, cellular excitotoxicity, demyelination, and free radical-mediated peroxidation and ensuing cell death. In this chapter, we review traditional avenues of drug therapy following traumatic SCI including methylprednisolone, naloxone, and monosialotetrahexosyl (GM-1) ganglioside. We also discuss pharmacotherapy options currently under investigation for the treatment of SCI, with attention given to those that are actively under human clinical trials: riluzole, minocycline, Rho protein antagonist, magnesium chloride in polyethylene glycol formulation, granulocyte colony stimulating factor (G-CSF), and fibroblast growth factor (FGF), and lithium. Far more work remains to be done to further characterize the efficacy, safety, and practicability of these pharmaceutical therapies.

Essential tremor (ET) is one of the most common movement disorders. The classification of ET and its uniform diagnosis have become subjects of intense debate. ET does not have a diagnostic marker. The diagnosis of ET depends on history, clinical examination, and exclusion of mimicking illnesses. There is strong evidence that ET is a hereditary disorder, but the gene defect is elusive. Making the correct diagnosis greatly impacts treatment. ET affects the hands or the hands in combination with head tremor. Isolated tremor elsewhere, such as of the head, tongue, lips, voice or face may be seen less commonly. Such heterogeneity sometimes pointed to discussions whether ET may be maintained as a unified disease entity. The tremor in ET is present when the muscles are rhythmically and abnormally activated, resulting in postural and/or kinetic tremor. Upon careful clinical examination, many patients with ET are found to have signs of cerebellar impairment, such as impairment of tandem stance and gait, as well as goal directed tremor. But action tremor is the predominant finding on clinical examination at any stage of ET. Other neurological deficits such as rigidity, bradykinesia or dystonia should prompt alternative diagnoses. The most important differential diagnoses of ET are enhanced physiologic tremor, idiopathic Parkinson’s disease, dystonic tremor, Wilson disease, orthostatic tremor, and psychogenic tremor. Many ET patients do not require treatment as the tremor does not impair daily functioning. If treatment is required, beta-blockers and/or anticonvulsive drugs are the first treatment options. Deep Brain Stimulation is a treatment for ET patients who are impaired in their daily life because of tremor and who did no benefit from drug treatment.

Improving living conditions and health care in developed countries has significantly increased life expectancy, which has led to an increase in age related disorders. In the population older than 60 years old the majority of cases of dementia are Alzheimer disease (AD). Progressive neurodegeneration in AD induces cognitive deterioration and constitutes a serious social problem. Currently, the drugs approved for the treatment of AD just slow down the progression of the disease or have a symptomatic effect. They are mainly acetylcholinesterase inhibitors (AChEIs) as donepezil, rivastigmine and galantamine or NMDA-receptor antagonist such as memantine. These drugs modestly improvement cognition, daily life activities and behavior in patients ranging from mild to severe stages of the disease. However, none of these agents has proven to be able to stop or reverse the underlying neurodegenerative process. Different studies point out that environmental factors and life style, such as diet and exercise have an important role in the biological mechanisms of the pathophysiology, considering them mutable. Actually, dietary compounds have been studied as therapeutics for neurodegenerative diseases and numerous studies have been focused on different nutritional approaches to benefit AD patients. On the other hand, during decades, medicinal plants have been studied as a potential treatment for dementia. This chapter includes a review of different natural products such as fatty acids, vitamins, alkaloids, amino acids, hormones and diverse groups of polyphenolic plant secondary metabolites, among others, which have a potential role in the prevention or treatment of AD.

It is estimated that some 25-30% of the population in the United States have experienced chronic pain. Worldwide, estimates reflect values of 35-40%. Chronic pain prevalence figures intensify the treatment approaches to care. Both pharmacological and non-pharmacological care is provided to address pain discomfort—oftentimes, at an individualized level. Relatively new strategies of prescribing additional pain management prescriptions of anti-depressant medications have enhanced the quality of care of the chronic pain patient. Sensory inputs from ascending pathways to the brain are targeted by pain medications. The common pathway to the cerebrum, at the periaqueductal gray which is largely noradrenergic and serotonergic, provides an additional platform to provide pharmacological treatment to the chronic pain patient. Anti-depressant medications act in many regions of the brain including the periaqueductal area. The resultant modulation of pain serves to also enhance the perception of pain relief from other pain medications. The adjuvant pain management treatment of anti-depressant medications is presented in terms of the types of chronic pain treated, the proposed mechanism of action of the antidepressant medications, and the other medications used in conjunction with anti-depressant medications.

Biosensors are devices that are composed of recognition element of primary biological nature or mimicking natural receptors, transducer that converts primary chemical signal into the measured physical value (current or voltage) and analyzer that evaluates the physical signal and allows preparing plot of the sensor response vs. the concentration of an analyte. Advantage of the biosensor over traditional analytical techniques, such as chromatography, mass spectroscopy and others is its ease of use, fast response and direct detection of analyte without additional labeling. Current trends are focused on using artificial receptors such as calixarenes and DNA/RNA aptamers for recognition of the molecules significant in medical diagnostics, in particularly, related to neurological disorder. This chapter reviews current state of the art in biosensor development toward detection of neurotransmitters using calixarenes and aptamers as well as prion diseases by DNA aptamer-based biosensors. Biosensors for early diagnostics of Alzheimer's disease are considered with particular emphasis to the optical and electrochemical detection. The detection of appropriate biomarkers, e.g., beta- amyloids, tau and ApoE proteins and miRNA in cerebrospinal fluid and blood is characterized from the point of view of biochemical recognition and signal generation principles. Besides, the problem of screening and sensitive detection of Alzheimer's disease drugs based on their anti-cholinesterase effect is discussed with examples of appropriate biosensors.

The N-methyl-D-aspartate receptor (NMDAR) is a glutamate receptor that mediates important physiological functions in the central nervous system (CNS). However, the overstimulation of this receptor is associated with neurodegenerative disorders, including Parkinson, Huntington and Alzheimer diseases. In this new millennium, diseases causing progressive neuronal loss and death have become more frequent and the current therapy still presents several adverse effects and does not block disease progression. In this chapter, we discuss the role of NMDAR in neurodegenerative disorders and its potential as a therapeutic target, the advances in the development of NMDAR antagonists and the contributions of molecular modeling in this field. NMDAR structure is already known allowing the use of molecular modeling tools for the development of new NMDAR antagonists. Studies involving the use of structure based drug-design methods as molecular docking and virtual screening for discovering new NMDAR antagonists were reviewed here; as well as the in silico evaluation of pharmacokinetic and toxicological properties. CNS drugs should be capable of effectively cross the blood brain barrier to be active and the early evaluation of the safety profile of these compounds is extremely important to reduce the time and costs to develop new drugs for neurodegenerative disease therapy.

Depression represents an assorted mood disorder, which has been recognized as a global issue. According to statistics, the life style of millions of individuals is distorted by mental or behavioral disorder. Prompt medicinal intervention is extremely required in major depression as millions of patients are reported for suicidal attempt each year. In clinics, several synthetic agents are in practice for the treatment of various types of depression, but their uses have been facing several limitations like slow onsite of action, efficacy in wide-range patients, side effects/toxicity etc. Unlike synthetic therapeutics, phytopharmaceuticals are extensively used world-wide due to their diverse applications, efficacious, and minimum side effects which lead to patient compliance. The alkaloids are indeed the most widely distributed and studied plant secondary metabolites that have established therapeutic history. This book chapter is primarily based on preclinical studies of various isolated alkaloids, their underlying possible mechanism(s) where discussed, structural edges and future directions towards clinical trials for the discovery of new effective and acceptable antidepressants.