Mental health and psychosocial support interventions for individuals affected by gender-based violence in fragile contexts: A systematic review.

Huntington’s disease (HD) is a genetically dominant neurodegenerative disorder that leads to progressive cognitive and motor decline and poses serious challenges for patients, families, and healthcare providers. In response to these challenges, researchers are working to understand disease mechanisms and develop new therapies. One area that has garnered significant attention is the role of cholesterol in brain function and its potential implication in HD pathogenesis. As a cholesterol-rich organ, the brain relies heavily on this crucial molecule to maintain its structure and function. Cholesterol is a vital component of myelin sheaths and cell membranes and plays a pivotal role in signal transduction and overall neuronal health. Because the blood–brain barrier (BBB) prevents cellular uptake of lipids from the bloodstream, the brain’s need for cholesterol is met by de novo cholesterol synthesis []. Interestingly, extensive research has identified significant impairments in cholesterol biosynthesis within the brain in various HD animal models, leading to reduced brain cholesterol levels in later disease stages. Notably, cholesterol biosynthesis is also affected in the presymptomatic stage of the disease, suggesting that cholesterol dysregulation may be an early event in HD pathogenesis [–]. The discovery of the potential role of cholesterol in HD has led to the development of two distinct therapeutic approaches. The first is based on enhancing cholesterol availability in the brain [–], and the second relies on promoting neuronal cholesterol catabolism through forced expression of the neuronal enzyme, cholesterol 24-hydroxylase (CYP46A) [, ]. Although these two cholesterol-based approaches may appear opposite, they converge on the same therapeutic goal: the restoration of cholesterol metabolism, which is consistently beneficial across different HD mouse models, underscoring their therapeutic potential. Here, we followed the first approach, but a major challenge lies in delivering cholesterol effectively to the brain. While crucial for maintaining the brain’s homeostasis, the BBB presents a significant obstacle to drug delivery to the central nervous system (CNS). Most peripherally administered drugs, such as those delivered via intraperitoneal injection, have limited access to the CNS and often undergo metabolism and clearance before reaching their target, thus diminishing their efficacy. This limitation has spurred the search for alternative delivery methods to bypass the BBB and directly target the brain. Given these challenges, we explored non-invasive strategies to deliver cholesterol to the CNS. Among these strategies, intranasal delivery has emerged as a promising approach. The neuroepithelium of the olfactory region provides a unique interface between the peripheral environment and the brain and so offers a potential route for drug delivery that bypasses the BBB. Drug transport from the nasal cavity to the CNS can occur through multiple pathways, including the olfactory and trigeminal nerve pathways and other routes involving vasculature, cerebrospinal fluid and the lymphatic system [, ]. Therefore, drugs for nose-to-brain delivery must have appropriate viscosity, physiological tonicity, and pH compatible with the nasal mucosa [–]. Different strategies have been studied. Particularly, nanoparticulate approaches, such as liposomes, have demonstrated a high capacity to overcome the challenges of the intranasal route. These approaches allow drug accumulation in the brain while avoiding systemic side effects. In recent years, liposomes have been utilized as carriers for vaccines, drugs, and tracers for imaging, as well as for administering molecules used in diagnosing and treating neurological diseases [].