Ibuprofen enhances synaptic function and neural progenitors proliferation markers and improves neuropathology and motor coordination in Machado–Joseph disease models

Abstract

Machado–Joseph disease or spinocerebellar ataxia type 3 is an inherited neurodegenerative disease associated with an abnormal glutamine over-repetition within the ataxin-3 protein. This mutant ataxin-3 protein affects several cellular pathways, leading to neuroinflammation and neuronal death in specific brain regions resulting in severe clinical manifestations. Presently, there is no therapy able to modify the disease progression. Nevertheless, anti-inflammatory pharmacological intervention has been associated with positive outcomes in other neurodegenerative diseases. Thus, the present work aimed at investigating whether ibuprofen treatment would alleviate Machado–Joseph disease. We found that ibuprofen-treated mouse models presented a significant reduction in the neuroinflammation markers, namely Il1b and TNFa mRNA and IKB-α protein phosphorylation levels. Moreover, these mice exhibited neuronal preservation, cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement. Additionally, neural cultures of Machado–Joseph disease patients’ induced pluripotent stem cells-derived neural stem cells incubated with ibuprofen showed increased levels of neural progenitors proliferation and synaptic markers such as MSI1, NOTCH1 and SYP. These findings were further confirmed in ibuprofen-treated mice that display increased neural progenitor numbers (Ki67 positive) in the subventricular zone. Furthermore, interestingly, ibuprofen treatment enhanced neurite total length and synaptic function of human neurons. Therefore, our results indicate that ibuprofen reduces neuroinflammation and induces neuroprotection, alleviating Machado–Joseph disease-associated neuropathology and motor impairments. Thus, our findings demonstrate that ibuprofen treatment has the potential to be used as a neuroprotective therapeutic approach in Machado–Joseph disease.

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

“…Thus, we cannot exclude that trehalose effects might occur, or at least count with contribution of indirect effects in peripheral energy metabolism and inflammatory pathways [55,56]. Therapeutic strategies that improves metabolism energy and inflammation, such as caloric restriction [22] and ibuprofen [57], are indeed effective in MJD mouse models. Interestingly, trehalose can also affect gut microbioma [58] , which raise the hypothesis that trehalose might interfere by modulating the microbiota-gut-brain axis.…”

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

“…The non-steroidal anti-inflammatory drug ibuprofen [37] has also been examined in SCA3/MJD models and shown to improve neuropathology and motor coordination concomitant with reductions in the neuroinflammatory markers interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and phosphorylated IKB-α. Ibuprofen has been examined in clinical trials for AD and found to reduce delta rhythm progression in mild cases [89].…”

Synthesis of New 1,2,3,4-Tetrahydroquinoline Hybrid of Ibuprofen and Its Biological Evaluation

“…Ibuprofen, on the other hand, is maybe the most popular non-steroidal anti-inflammatory drug, used in the treatment of many musculoskeletal disorders [11], and is the safest traditional choice for utilization during chronic neuroinflammation such as in Alzheimer's [12], Parkinson's [13], and Machado-Joseph disease [14]. Hybrids of ibuprofen with quinoline are interesting [11] in order to study their potential biological Likewise, the 1,2,3,4-tetrahydroquinoline skeleton is prevalent in many pharmacologically active synthetic and natural products [9].…”