Dexamethasone in glioblastoma multiforme therapy : mechanisms and controversies

Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.peer-reviewe

The emerging role of the inwardly rectifying K+ channels in autism spectrum disorders and epilepsy

Autism is a complex behavioral disorder that develops prior to age three years and is distinguished by high heritability. Many genes predisposing to autism spectrum disorders (ASDs) have been identified. These findings have demonstrated that ASDs are etiologically heterogeneous; although, the mutations underlying ASDs are identifiable only in a minority of patients. Indeed, the causes of ASDs are unknown in more than 70% of patients. Recently, we have described two unrelated families whose affected individuals display a characteristic triad of symptoms of autism; such as impairments in social interaction, impairments in communication, restricted interests and repetitive behavior. They also displayed other symptoms commonly observed in autistic individuals; such as gait imbalance, clumsiness, mental retardation and epilepsy. The genetic analysis of these families resulted in the identification of new heterozygous point mutations in the KCNJ10 gene that encodes the inwardly-rectifying K+ channel Kir4.1 expressed predominantly, but not exclusively, in astrocytes. Functionally, the mutated channels exhibited a phenotype consistent with gain-of-function defects. These new findings highlight the emerging role of inwardly-rectifying K+ channels and astrocyte dysfunction in autism spectrum disorders associated with epilepsy.peer-reviewe

Redox sensitivity of tyrosine hydroxylase activity and expression in dopaminergic dysfunction

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson’s disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression. The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.peer-reviewe

Autism spectrum disorder

Background: Autism spectrum disorder is a complex heterogeneous condition that is characterized by impairments in social interaction, communication, and behavior which mostly co-exists with several comorbidities. The current prevalence of autism spectrum disorder in the general population is estimated to be 1 in 68 children. Despite significant advances in research and multiple treatment options, the management of the disease remains poor. Although there are governmental services and few non-governmental organizations working for individuals with autism, there is no official data available regarding the incidence and prevalence of autism in Malta Methods: This study focuses on the need of increasing awareness for autism spectrum disorder in Malta among the general public and health care professionals which would benefit a better understanding of the disorder for early diagnosis and more effective treatments. This was best provided through questionnaires. Results: Our survey revealed that only a limited percentage of the Maltese population had some knowledge about the symptoms, age of onset, potential causes of the disease and treatment options for autism. Conclusion: There is an immense need for improvement regarding the awareness of autism in Malta to estimate the exact burden of the disorder and make the latest diagnostic and treatment options available to the people living with this disease on the island

Techniques in Neuroscience

Microdialysis cerebral technique has been widely employed in order to study neurotransmitter release. This technique presents numerous advantages such as it allows work with sample in vivo from freely moving animals. Different drugs in different points implanted probes in several brain areas can be infused simultaneously by means of microdialysis. Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopamine (DA) neurons in the nigrostriatal system, which in turn produces profound neurochemical changes within the basal ganglia, representing the neural substrate for Parkinsonian motor symptoms. Over the years, a broad variety of experimental models of the disease have been developed and applied in diverse animal species. The two most common toxin models used employ 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenilpyridinium ion (MPTP/MPP+), either given systemically or locally applied into the nigrostriatal pathway, to resemble PD features in animals. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, although with different mechanisms. Since in vivo microdialysis coupled to high-performance liquid chromatography (HPLC) is an established technique for studying physiological, pharmacological, and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid, here we describe a rapid and simple microdialysis technique that allows the direct quantitative study of the damage produced by 6-OHDA and MPP+ toxins on dopaminergic (DAergic) striatal terminals of rat brain.peer-reviewe

Ion Channels Involvement in Neurodevelopmental Disorders

Inherited and sporadic mutations in genes encoding for brain ion channels, affecting membrane expression or biophysical properties, have been associated with neurodevelopmental disorders characterized by epilepsy, cognitive and behavioral deficits with significant phenotypic and genetic heterogeneity. Over the years, the screening of a growing number of patients and the functional characterization of newly identified mutations in ion channels genes allowed to recognize new phenotypes and to widen the clinical spectrum of known diseases. Furthermore, advancements in understanding disease pathogenesis at atomic level or using patient-derived iPSCs and animal models have been pivotal to orient therapeutic intervention and to put the basis for the development of novel pharmacological options for drug-resistant disorders. In this review we will discuss major improvements and critical issues concerning neurodevelopmental disorders caused by dysfunctions in brain sodium, potassium, calcium, chloride and ligand-gated ion channels

Episodic ataxia type 1

Clinical characteristics: Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other findings can include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence. Diagnosis/testing: Diagnosis is based on clinical findings, an electrophysiologic test of axonal superexcitability and threshold electrotonus, and/or molecular genetic testing of KCNA1, the only gene in which pathogenic variants are known to cause EA1. Management: Treatment of manifestations: Acetazolamide (ACTZ), a carbonic-anhydrase (CA) inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Antiepileptic drugs (AEDs) may significantly reduce the frequency of the attacks in some individuals.peer-reviewe

The role of ion channels in the hypoxia-induced aggressiveness of glioblastoma

The malignancy of glioblastoma multiform (GBM), the most common and aggressive form of human brain tumors, strongly correlates with the presence of hypoxic areas, but the mechanisms controlling the hypoxia-induced aggressiveness are still unclear. GBM cells express a number of ion channels whose activity supports cell volume changes and increases in the cytosolic Ca2+ concentration, ultimately leading to cell proliferation, migration or death. In several cell types it has previously been shown that low oxygen levels regulate the expression and activity of these channels, and more recent data indicate that this also occurs in GBM cells. Based on these findings, it may be hypothesized that the modulation of ion channel activity or expression by the hypoxic environment may participate in the acquisition of the aggressive phenotype observed in GBM cells residing in a hypoxic environment. If this hypothesis will be confirmed, the use of available ion channels modulators may be considered for implementing novel therapeutic strategies against these tumors.peer-reviewe

Update on the implication of potassium channels in autism : K+ channelautism spectrum disorder

Autism spectrum disorders (ASDs) are characterized by impaired ability to properly implement environmental stimuli that are essential to achieve a state of social and cultural exchange. Indeed, the main features of ASD are impairments of interpersonal relationships, verbal and non-verbal communication and restricted and repetitive behaviors. These aspects are often accompanied by several comorbidities such as motor delay, praxis impairment, gait abnormalities, insomnia, and above all epilepsy. Genetic analyses of autistic individuals uncovered deleterious mutations in several K+ channel types strengthening the notion that their intrinsic dysfunction may play a central etiologic role in ASD. However, indirect implication of K+ channels in ASD has been also reported. For instance, loss offragile X mental retardation protein (FMRP) results in K+ channels deregulation, network dysfunction and ASD-like cognitive and behavioral symptoms. This review provides an update on direct and indirect implications of K+ channels in ASDs. Owing to a mounting body of evidence associating a channelopathy pathogenesis to autism and showing that nearly 500 ion channel proteins are encoded by the human genome, we propose to classify ASDs - whose susceptibility is significantly enhanced by ion channels defects, either in a monogenic or multigenic condition - in a new category named “channelAutismSpectrumDisorder”(channelASD; cASD) and introduce a new taxonomy (e.g., Kvx.y-channelASD and likewise Navx.y-channelASD, Cavx.y-channelASD; etc.). This review also highlights some degree of clinical and genetic overlap between K+ channelASDs and K+ channelepsies, whereby such correlation suggests that a subcategory characterized by achannelASD-channelepsy phenotypemay be distinguished. Ultimately, this overview aims to further understand the different clinical subgroups and help parse out the distinct biological basis of autism that are essential to establish patient-tailored treatments.peer-reviewe