Past, present and future therapeutics for cerebellar ataxias

Abstract

Cerebellar ataxias are a group of disabling neurological disorders. Patients exhibit a cerebellar syndrome and can also present with extra-cerebellar deficits, namely pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. Recently, deficits in cognitive operations have been unraveled. Cerebellar ataxias are heterogeneous both at the phenotypic and genotypic point of view. Therapeutical trials performed during these last 4 decades have failed in most cases, in particular because drugs were not targeting a deleterious pathway, but were given to counteract putative defects in neurotransmission. The identification of the causative mutations of many hereditary ataxias, the development of relevant animal models and the recent identifications of the molecular mechanisms underlying ataxias are impacting on the development of new drugs. We provide an overview of the pharmacological treatments currently used in the clinical practice and we discuss the drugs under development.

Keywords: Cerebellum; X-linked; ataxias; dominant; recessive; therapy..

Fig. (1)

Representation of the connectivity of cerebellar neurons and expression of receptors. Two categories of inputs reach the cerebellar cortex: (1) the mossy fibers targeting granule cells and cerebellar nuclei (DCN), and (2) the climbing fibers originating from the inferior olivary complex (IO) and projecting to cerebellar nuclei and Purkinje neurons. Granule cells give rise to parallel fibers which make numerous synapses with dendritic spines of Purkinje cells. Inhibitory interneurons of the cerebellar cortex include basket cells, stellate cells and Golgi cells. Abbreviations: AMPA: aminohydroxymethylisoxazoleproprionate, NMDA: N-methyl-D-aspartate, mGluR. GABAA: GABA-A receptor, GABAB: GABA-B receptor, 5-HT: serotonin, CB1: cannabinoid 1 receptor.

Fig. (2)

Mechanism of action of N-acetylcysteine (NAC). ASC, alanine-serine-cysteine (ASC) transport system; c-GCS, c-glutamylcysteine synthetase; cys, cysteine; glu, glutamine; gly, glycine; GSH, glutathione. Adapted from Arakawa and Ito (2007), [9].

Fig. (3)

Potential routes of mitochondrial HNE metabolism. HNE is able to alkylate diverse classes of biological molecules. Balancing this toxicity is the metabolism of HNE by multiple phase I and phase II pathways. GS-HNE and GS-HNE acid can dehydrate to form a cyclic hemiacetal and lactone, respectively. Adapted from Arakawa and Ito 2007, [9].

Fig. (4)

Schematic rappresentation of the metabolism of Idebenone. Idebenone is absorbed and can be converted via the oxidative shortening or directly being conjugated. The structure of ubiquinone is shown on the upper right corner.

Fig. (5)

Molecular structures of current drugs assessed for therapy of cerebellar disorders.

Fig. (6)

Illustration of the sites of action of anti-ataxic drugs. Drugs can be gathered in 4 groups according to the mechanism of action: modulation of synaptic activity, action against oxidative stress, acting on the DNA/RNA level, and targeting the clearance of specific proteins.