Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis

Abstract

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease.

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

“…However, the full spectrum of A-T immune deficiencies has proven to be broader than this, and the mechanisms linking immune deficiencies to the neurological symptoms are not well understood. Previous findings have shown that in both human A-T and its mouse models, anti-inflammatory betamethasone treatments blunt the severity of the neurological symptoms (Menotta et al, 2012;Zannolli et al, 2012;Giardino et al, 2013). These findings have been extended to mice; NSAIDs blocked the appearance of some cell biological symptoms of Atm -/mice: the activation of the brain Figure 9.…”

Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2‐mediated antioxidant response

“…Although the lifespan of patients with A-T has been prolonged over the years, no established therapy is currently available. Recently, the glucocorticoid analogues betamethasone and dexamethasone (DEXA) have been successfully proposed as a novel treatment for A-T patients [29][30][31][32][33][34][35][36], although their mechanisms of action are still under investigation [37,38]. We have previously reported that DEXA can partially rescue ATM deficiency by promoting a shortened protein variant [39].…”

Ataxia-telangiectasia: future prospects

“…Of note, ATM signaling appears to function predominantly in immature recently post-mitotic neurons to trigger apoptosis of cells that have experienced excess DNA damage during brain development 55. Even though steroids are not curative and cannot be proposed for long-term therapies due to their side effects, it is suggested that during the clinical course there is a phase when neurological impairment can be rescued to some extent 56. In a multicenter, double-blind, randomized, placebo-controlled, crossover trial, oral betamethasone use showed significant reduction in ataxia scores 57.…”