Frontiers in Clinical Drug Research - CNS and Neurological Disorders

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) frequently starting in young adulthood. However, the pathogenesis of the progressive disease phase is still not well-understood, and the inflammation as well as the mechanisms of demyelination and tissue damage is currently being discussed. The available drugs approved in the treatment of different clinical forms of MS prevent the relapses, alleviate the symptoms only partially and slow progression of the disease; however, none of these treatments is capable in stopping the MS clinical course. Moreover, approved MS treatments lead to unpredictable adverse effects associated with a range from mild (such as flu-like symptoms, fatigue, liver transaminase elevation, stomach pain or irritation at an injection site) to serious (such as bradycardia or progressive multifocal leukoencephalopathy). It is time to revise the MS drug development strategy by relying on our endogenous defense mechanisms. Endogenous fatty acid amides (FAAs) are a family of structurally different molecules found in mammalian systems. These compounds include anandamide, oleoylethanolamide and palmitoylethanolamide; research preclinical and clinical reported anti-inflammatory and neuroprotective activity of FAAs making them an alternative therapeutic approach in neurological disorders. In consideration that an endogenous compound able in the control of endogenous defense mechanisms can assume extraordinary importance, this chapter includes a discussion on current approved drugs in MS, and on pharmacological properties of FAAs that may play a promising role in complementing of medication approved for use in MS.

The use of transformation techniques (such as a wavelet transform, Fourier transform, or hybrid transform) to detect epileptic seizures by means of EEG signals is not adequate because these signals have a nonstationary and nonlinear nature. This paper reports on the design of a novel technique based, instead, on the domain of graphs. The dimensionality of each single EEG channel is reduced using a segmentation technique, and each EEG channel is then mapped onto an undirected weighted graph. A set of structural and topological graph characteristics is extracted and investigated, and several machine learning techniques are utilized to categorize the graph’s attributes. The results demonstrate that the use of graphs improves the quality of epileptic seizure detection. The proposed method can identify EEG abnormities that are difficult to detect accurately using other transformation techniques, especially when dealing with EEG big data.

Essential tremor (ET) is one of the most prevalent neurological disorders worldwide. ET presents mainly with kinetic and action tremor in upper limbs. Tremor may also affect the head and some patients develop an ataxic gait, as well as cognitive/affective symptoms. ET significantly impacts the quality of life. There is accumulating evidence that ET is a slowly progressive neurodegenerative disease, driven by both genetic and environmental (possibly dietary) factors. Both the olivocerebellar pathways and the cerebellar cortex are critically involved, with particular impairments in the morphology of the Purkinje neurons (Purkinjopathy) as well as the surrounding micro-circuitry. Dysfunctional cerebello-thalamo-cortical loops probably result in bursts of tremor. So far, only few symptomatic medications are available, including beta-blockers, primidone and drugs aiming to modulate GABAergic transmission such as topiramate or gabapentine. Surgery (deep brain stimulation, thalamotomy) is proposed to refractory cases but carries the risk of infection, bleeding in the brain and several technical issues related to the mispositioning of electrodes. MRI-guided focused ultrasound is a promising technique, but long-term follow-up is missing. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are encouraging non-invasive techniques but no consensus on optimal protocols has been reached so far. It is remarkable to observe that none of the available therapies targets the neurodegenerative process affecting in particular the cerebellum, the masterpiece of progression of the disease. This chapter focuses on the pathogenesis of ET and discusses possible novel avenues for therapy and prevention. In particular, the impact of environmental toxins such as beta-carboline alkaloids (βCAs), possibly generated from Maillard-type reaction products, is discussed. Animal models of ET, toxicokinetics and neurotoxic effects of βCAs are presented, with an emphasis on the neuroprotective pathways that are candidates to block the neurodegenerative process. Moreover, we consider a group of enzymes that could be neuroprotective, especially GAD65 and GAD67, involved in GABA synthesis/neurotransmission, and MAOA/MAOB. Finally, we emphasize the potential interest of dietary phytochemicals (such as phenolic acids, catechins, flavonoids, anthocyans, stilbenoids, curcuminoids) and herbal therapies (based i.e. on Bacopa monnieri, Ginkgo biloba) as neuroprotective approaches to hamper the neurodegenerative process in ET.

Pharmacoresistant epilepsy is estimated to affect about 30% of patients with epilepsy and predisposes to a higher risk for psychiatric comorbidities and depression. This is one of the most common complications in epilepsy but the mechanisms underlying its development are still unclear. Periclinical studies have shown that selective serotonin reuptake inhibitors (SSRIs) are ineffective against comorbid depression. Dysfunction in circadian rhythms which are driven by the suprachiasmatic nucleus (SCN), is a hallmark of depression. The activity of this circadian pacemaker is under the fine-tuning control of the endogenous hormone melatonin. Over the past decade, there has been extensive research on the therapeutic potential of melatonin and its analogues in the management of both epilepsy and depressive disorders. Melatonin and its analogues targeting the melatonin MT1 and MT2 receptors are considered as potential adjuvants for the treatment of epilepsy associated with moderate-to-strong antioxidant, anti-inflammatory, and neuroprotective activity at non-toxic doses. One of the main advantages of the melatonin system is associated with its chronobiotic properties and pivotal role in the resynchronization of disturbed circadian rhythms of different parameters. This chapter summarizes the available experimental and clinical data on melatonin and drugs acting on the MT receptors, which are currently of therapeutic interest in the treatment of epilepsy and depression. Despite the fact that melatonin and drugs based on MT receptors have been used for many purposes over the last three decades, the available data on the potential implementation of melatonin compounds in epilepsy and comorbid depression are scarce. The many unanswered questions regarding the use of melatonin to treat epileptic seizures and complications associated with epilepsy are briefly summarized.

From the past several decades, neuroscientists have been focusing on understanding the mechanisms of various human neurodegenerative diseases using different models such as Mouse, Rat, Zebrafish, worm and the Drosophila. Among them, the Drosophila, with a short generation time and genetic amenity, has emerged as a vital and prevailing model system to explore multiple aspects of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, etc. In this chapter, we have presented various molecular, genetic and therapeutic approaches employed to model human neurodegenerative diseases using Drosophila. Furthermore, we also present the worldwide prevalence of neurodegenerative diseases, along with a survey of published literatures of research conducted in the last two decades on major neurodegenerative diseases employing transgenic Drosophila, to evaluate where we stand.

Stroke is a complex disease resulting from a combination of vascular, environmental and genetic factors. Different therapeutic strategies for the treatment of stroke include antiplatelet therapy, anticoagulants, and lipid- lowering drugs. These drugs act via diverse mechanisms of action and target specific enzymes. The enzymes increase the levels of ubiquitous secondary molecules that can cause changes in vascular tone, increase platelet aggregation, cholesterol levels, and other cellular events. Several inhibitors have been developed to curb these enzymes and thus prevent a recurrent stroke. The most potent inhibitors given in the stroke treatment include inhibitors of angiotensin-converting enzyme (ACE) (perindopril, ramipril), phosphodiesterases (PDEs) (rolipram), GpIIb/IIIa and 3-hydroxy-3-methyl-glutryl- coenzyme A reductase (HMG-CoA reductase) (pravastatin). ACE inhibitors block the ACE enzyme, thereby preventing the conversion of inactive decapeptide angiotensin I to the active octapeptide and potent vasoconstrictor angiotensin II. Angiotensin II plays a pivotal role in the development of hypertension, atherosclerosis and thrombotic events like stroke. Other inhibitors like phosphodiesterase inhibitors (PDEIs) prevent the inactivation of intracellular mediators of signal transduction such as cAMP and cGMP. These mediators are critical to the regulation of platelet functions. PDEIs are used as antiplatelet agents in clinical settings. Statins are given as lipidlowering drugs to reduce the risk of stroke by decreasing blood cholesterol levels through inhibition of liver enzyme β-hydroxymethyl glutaryl coenzyme A reductase enzyme. The current chapter will focus on the recent developments in stroke treatment, especially focussing on potent inhibitors such as PDE, ACE, and HMG.