Imidazoline receptors as a new therapeutic target in Huntington’s disease: A preclinical overview

An autosomal dominant neurodegenerative disease called Huntington's disease (HD) is characterized by motor dysfunction, cognitive decline, and a variety of psychiatric symptoms due to the expansion of polyglutamine in the Huntingtin gene. The disease primarily affects the striatal neurons within the basal ganglia, leading to significant neuronal loss and associated symptoms such as chorea and dystonia. Current therapeutic approaches focus on symptom management without altering the disease's progression, highlighting a pressing need for novel treatment strategies. Recent studies have identified imidazoline receptors (IRs) as promising targets for neuroprotective and disease-modifying interventions in HD. IRs, particularly the I1 and I2 subtypes, are involved in critical physiological processes such as neurotransmission, neuronal excitability, and cell survival. Activation of these receptors has been shown to modulate neurotransmitter release and provide neuroprotective effects in preclinical models of neurodegeneration. This review discusses the potential of IR-targeted therapies to not only alleviate multiple symptoms of HD but also possibly slow the progression of the disease. We emphasize the necessity for ongoing research to further elucidate the role of IRs in HD and develop selective ligands that could lead to effective and safe treatments, thereby significantly improving patient outcomes and quality of life.