CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 17, Issue 3, 2018

Background & Objective: Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Many years have passed since the description of the Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described. The genetic mutations mostly result in the accumulation of toxic metabolites which causes Purkinje neuron lost and eventual cerebellar dysfunction. Unfortunately, the recessive ataxias remain a poorly known group of diseases and most of them are yet untreatable. Conclusion: The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich's ataxia, Ataxia-telangiectasia, Wilson's disease and Niemann-Pick disease in the next few years.

Background & Objective: Neurotransplantation has been recently the focus of interest as a promising therapy to substitute lost cerebellar neurons and improve cerebellar ataxias. However, since cell differentiation and synaptic formation are required to obtain a functional circuitry, highly integrated reproduction of cerebellar anatomy is not a simple process. Rather than a genuine replacement, recent studies have shown that grafted cells rescue surviving cells from neurodegeneration by exerting trophic effects, supporting mitochondrial function, modulating neuroinflammation, stimulating endogenous regenerative processes, and facilitating cerebellar compensatory properties thanks to neural plasticity. On the other hand, accumulating clinical evidence suggests that the self-recovery capacity is still preserved even if the cerebellum is affected by a diffuse and progressive pathology. We put forward the period with intact recovery capacity as “restorable stage” and the notion of reversal capacity as “cerebellar reserve”. Conclusion: The concept of cerebellar reserve is particularly relevant, both theoretically and practically, to target recovery of cerebellar deficits by neurotransplantation. Reinforcing the cerebellar reserve and prolonging the restorable stage can be envisioned as future endpoints of neurotransplantation.

Background: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cerebellar reserve remains. Objective: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view. Method: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, regardless of the region. Therefore, the cerebellar reserve may be defined as a mechanism to restore its proper input-output organization of the cerebellar neuron circuitry, when it is damaged. Then, the following four components are essential for recruitment of the cerebellar reserve: operational local neuron circuitry; proper combination of mossy fiber inputs to be integrated; climbing fiber inputs to instruct favorable reorganization of the integration; deep cerebellar nuclei to generate reorganized outputs. Results: We discussed three topics related to these resources, 1) principles of generating organized cerebellar outputs, 2) redundant mossy fiber inputs to the cerebellum, 3) plasticity of the cerebellar neuron circuitry. Conclusion: To make most of the cerebellar reserve, it is desirable to start any intervention as early as possible when the cerebellar cell loss is minimal or even negligible. Therefore, an ideal future therapy for degenerative cerebellar diseases should start before consuming the cerebellar reserve at all. In the meantime, our real challenge is to establish a reliable method to identify the decrease in the cerebellar reserve as early as possible.

Background & Objective: Non-invasive brain stimulation (NIBS) might be a valuable therapeutic approach for neurological diseases by modifying the cortical activity in the human brain and promoting neural plasticity. Currently, researchers are exploring the use of NIBS on the cerebellum to promote functional neural changes in cerebellar disorders. In the presence of cerebellar dysfunction, several movement disorders, such as kinetic tremor, ataxia of gait, limb dysmetria and oculomotor deficits, become progressively more disabling in daily life, and no pharmacological treatments currently exist. Conclusion: In the present mini-review, we report the main evidence concerning the use of NIBS in three specific cerebellar dysfunctions, cerebellar ataxias (CA), essential tremor (ET) and ataxic cerebral palsy, in which abnormalities of neuroplasticity and cortical excitability can be important pathophysiological factors.

Background & Objective: During the past 3 decades, numerous neurophysiological, neuroimaging, experimental and clinical studies have evidenced a crucial role for the cerebellum in cognitive, affective and behavioral functions. As a result of the acknowledged modulatory role of the cerebellum upon remote structures such as the cerebral cortex, cerebellar injury may give rise to a constellation of behavioral, affective and cognitive symptoms (Schmahmann's Syndrome). In sharp contrast to the wide range of therapeutic interventions to treat cognitive and affective disorders following cerebral cortical lesions and despite the consequences of Schmahmann's syndrome upon daily life activities, the literature is surprisingly only scantly documented with studies investigating the impact of cognitive therapies on cerebellar induced cognitive and affective disorders. This survey aims to present an overview of the therapeutic interventions available in the literature as a possible treatment for Schmahmann's Syndrome after cerebellar injury, after posterior fossa surgery in children, and in children with neurodevelopmental disorders. Although systematical studies are clearly warranted, available evidence suggests that cerebellar-induced cognitive and affective disorders should be treated in a specific way. Approaches where the patients are explicitly made aware of their deficits and are considered to act as an “external cerebellum” are the most promising. Conclusion: The study of the anatomical connectivity of the cerebellar microcomplexes involved in cognitive/affective deficits is likely to play a major-role in the future.

Background: Neurodegeneration is a condition in which progressive loss of function and structure of neurons occurs. Several lines of evidence suggest that oxidative stress has a central role in neurodegenerative diseases. Objective: The aim was to survey molecular mechanisms underlying the involvement of oxidative stress in developing different neurodegenerative diseases. Methods: Original and review articles were retrieved through a PubMed and Google scholar search (from 1989 to 2015) using the following key words: “oxidative stress”, “nerve degeneration” and “neurodegenerative diseases”. Results: A comprehensive analysis of the obtained articles confirmed strong involvement of oxidative stress in the pathophysiology of neurodegenerative diseases through a variety of mechanisms including induction of oxidation of nucleic acids, proteins and lipids, formation of advanced glycation end products, mitochondrial dysfunction, glial cell activation, amyloid β deposition and plaque formation, apoptosis, cytokine production and inflammatory responses, and proteasome dysfunction. Conclusion: Regarding the pivotal role of oxidative stress in neurodegeneration, modulation of free radical production or alleviating their harmful effects can be considered as a potential therapeutic strategy for preventing and controlling neurodegenerative diseases. Accordingly; boosting endogenous antioxidant capacity besides providing exogenous sources of antioxidants merits future research in order to discover new therapeutic agents.

Background & Objective: A number of neuropsychiatric disorders, including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and, to some extent, depression, involve dysregulation of the brain dopamine systems. The etiology of these diseases is multifactorial, involving genetic and environmental factors. Evidence suggests that inadequate levels of n-3 (omega- 3) polyunsaturated fatty acids (PUFA) in the brain may represent a risk factor for these disorders. These fatty acids, which are derived from the diet, are a major component of neuronal membranes and are of particular importance in brain development and function. Low levels of n-3 PUFAs in the brain affect the brain dopamine systems and, when combined with appropriate genetic and other factors, increase the risk of developing these disorders and/or the severity of the disease. This article reviews the neurobiology of n-3 PUFAs and their effects on dopaminergic function. Conclusion: Clinical studies supporting their role in the etiologies of diseases involving the brain dopamine systems and the potential of n-3 PUFAs in the treatment of these disorders are discussed.

Purpose: This study was intended to observe electroencephalographic (EEG) changes and convulsion attacks in children receiving neural precursor cell transplantation, and to explore the possibility of electrophysiological changes and risk of convulsion occurrence after cell transplantation. Method: 228 children were included in this study who received neural precursor cell transplantation in our hospital between March 2008 and July 2012. No history of convulsion attacks was elicited before cell transplantation. Data about EEG change and convulsion occurrence before and after cell transplantation were analyzed statistically. Results: Of the 228 pediatric patients, EEG improvement, deterioration and no significant change were observed in 60, 45 and 122 patients, respectively. One month after transplantation, four (1.76%) patients experienced new convulsions. Of the 227 patients, 25 showed increased and/or abnormal discharges on EEG. Of these, 19 underwent EEG re-examination six months post-operation. Except the convulsive cases mentioned above, there were no new cases of convulsions in the remaining patients. Of the 27 patients including those with abnormal discharge, increased discharge and convulsion attacks, 17 achieved varying degrees of therapeutic efficacy. Conclusion: Intraventricular transplantation of neural precursor cells is associated with EEG changes in some children and clinical convulsion attacks in individual patients. However, these abnormal changes do not last long and usually return to normal levels within 1-6 months after surgery, along with disappearance of convulsions. Simultaneous occurrence of EEG changes and convulsions do not appear to affect therapeutic efficacy.