Beneficial effects of the investigational neuroprotective drug olesoxime have mainly been attributed to its effects on mitochondria, but new research suggests it also blocks calpain — a molecule directly involved in Huntington’s disease. The findings indicate that exploring the drug’s exact mechanism might bring scientists closer to effective treatments for Huntington’s.
Olesoxime (Roche Pharmaceuticals) has been extensively studied in preclinical models of neuroprotection, showing that it prevents what is known as the mitochondrial permeability transition — a mechanism allowing the release of high levels of substances that might be toxic to cells. Researchers believe that the improvement of mitochondrial function might restore a disrupted calcium balance, typically observed in neurodegenerative diseases.
When researchers from University of Tuebingen, Germany, tested olesoxime in a rat model of Huntington’s, they noted that the drug reduced both cognitive and psychiatric abnormalities, increased the thickness of the brain’s cortical layer, and reduced both aggregation and accumulation of mutant huntingtin. The prevention of protein aggregation seemed to be a result of a lower breakdown of mutant proteins by an enzyme called calpain, a crucial factor in the aggregation of huntingtin in this model.
In the study “The calpain-suppressing effects of olesoxime in Huntington’s disease,“ published in the journal Rare Diseases, the research team demonstrated that the drug also seems to be advantageous in another Huntington’s disease model — the HdhQ111 knock-in mouse.
This mouse, with the human mutant sequence inserted into its huntingtin gene, develops symptoms more closely resembling the human disease. At six months of age, the mutant mice had increased activity of calpain and increased huntingtin fragmentation, which was reduced by olesoxime treatment from before birth. The treatment, however, only had a marginal effect on protein aggregation.
Moreover, the changes were only observed in the striatum of the mice — a brain region crucial for the control of movements, and affected in Huntington’s disease. In contrast, the previously investigated rat model showed changes only in the cortex and not in the striatum.
Studies have suggested that olesoxime might influence calpain through changes in calcium, proposing that animal models of Huntington’s have a disrupted calcium balance. Researchers are currently investigating olesoxime’s effects on calcium in cultured cells from the striatum of the Huntington’s mouse model.
Given the differences of drug administration in various disease models, further animal studies exploring the exact mechanism of the drug and the interactions between mitochondrial function, calcium balance, calpain activation, and huntingtin fragmentation and aggregation are needed to allow the separation of these complex processes.