The autophagy‐enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado–Joseph disease

Abstract

Aims Machado–Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is the most common autosomal dominantly‐inherited ataxia worldwide and is characterised by the accumulation of mutant ataxin‐3 (mutATXN3) in different brain regions, leading to neurodegeneration. Currently, there are no available treatments able to block disease progression. In this study, we investigated whether carbamazepine (CBZ) would activate autophagy and mitigate MJD pathology. Methods The autophagy‐enhancing activity of CBZ and its effects on clearance of mutATXN3 were evaluated using in vitro and in vivo models of MJD. To investigate the optimal treatment regimen, a daily or intermittent CBZ administration was applied to MJD transgenic mice expressing a truncated human ATXN3 with 69 glutamine repeats. Motor behaviour tests and immunohistology was performed to access the alleviation of MJD‐associated motor deficits and neuropathology. A retrospective study was conducted to evaluate the CBZ effect in MJD patients. Results We found that CBZ promoted the activation of autophagy and the degradation of mutATXN3 in MJD models upon short or intermittent, but not daily prolonged, treatment regimens. CBZ up‐regulated autophagy through activation of AMPK, which was dependent on the myo‐inositol levels. In addition, intermittent CBZ treatment improved motor performance, as well as prevented neuropathology in MJD transgenic mice. However, in patients, no evident differences in SARA scale were found, which was not unexpected given the small number of patients included in the study. Conclusions Our data support the autophagy‐enhancing activity of CBZ in the brain and suggest this pharmacological approach as a promising therapy for MJD and other polyglutamine disorders.

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

“…Carbamazepine (CBZ, Tegretol ® , 5H-dibenzo[b,f]azepine-5-carboxamide) is an aromatic anticonvulsant that has been widely used for the treatment of seizure disorders and neuropathic pain specifically for trigeminal neuralgia [ 1 , 2 , 3 , 4 , 5 ]. This drug has been also demonstrated as an adjunctive treatment in schizophrenia or myotonia and as a second-line agent in bipolar disorder [ 6 , 7 , 8 , 9 , 10 ].…”

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms

“…Several attempts to correct autophagy in MJD have been made either by inducing the overexpression of ULK or beclin-1, or by administrating autophagy enhancing drugs, such as carbamazepine or trehalose, achieving good results. [109][110][111][112] A clear relationship between lysosomal dysfunction and autophagy impairments was established for LSDs. In fact, besides storage, there are many secondary effects caused by the dysfunction of the lysosomalautophagy machinery, such as exocytosis, cholesterol homeostasis and unbalance of crucial cellular pathways that are associated with the control of cell death, differentiation and proliferation or immune response (reviewed in 102 ).…”

“…117 It has been proposed that MSC control autophagy by playing an important role in down-regulating inflammation, apoptosis and oxidative stress in many different disease contexts. 110 Studies in other neurodegenerative disorders gave evidence that MSC can, in fact, promote autophagy and protein clearance. In in vivo models for Alzheimer's disease (AD), MSC transplantation promoted autophagosome induction, maturation of autophagic vacuoles and fusion with lysosomes and this was linked to the reduction of AB levels and neuronal preservation.…”

“…In MJD, autophagy is decreased by the accumulation of mutant ataxin‐3 that tends to form both soluble toxic fragments and insoluble aggregates. Several attempts to correct autophagy in MJD have been made either by inducing the overexpression of ULK or beclin‐1, or by administrating autophagy enhancing drugs, such as carbamazepine or trehalose, achieving good results 109‐112 . A clear relationship between lysosomal dysfunction and autophagy impairments was established for LSDs.…”

“…Remarkably, there is a recognizable link between MSC and autophagy regulation 117 . It has been proposed that MSC control autophagy by playing an important role in down‐regulating inflammation, apoptosis and oxidative stress in many different disease contexts 110 . Studies in other neurodegenerative disorders gave evidence that MSC can, in fact, promote autophagy and protein clearance.…”