Late-onset major depressive disorder: exploring the therapeutic potential of enhancing cerebral brain-derived neurotrophic factor expression through targeted microRNA delivery

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition that significantly impacts the overall quality of life. Although MDD can occur across all age groups, it is notably prevalent among older individuals, with the aggravating circumstance that the clinical condition is frequently overlooked and undertreated. Furthermore, older adults often encounter resistance to standard treatments, experience adverse events, and face challenges associated with polypharmacy. Given that late-life MDD is associated with heightened rates of disability and mortality, as well as imposing a significant economic and logistical burden on healthcare systems, it becomes imperative to explore novel therapeutic approaches. These could serve as either supplements to standard guidelines or alternatives for non-responsive patients, potentially enhancing the management of geriatric MDD patients. This review aims to delve into the potential of microRNAs targeting Brain-Derived Neurotrophic Factor (BDNF). In MDD, a significant decrease in both central and peripheral BDNF has been well-documented, raising implications for therapy response. Notably, BDNF appears to be a key player in the intricate interplay between microRNA-induced neuroplasticity deficits and neuroinflammation, both processes deeply implicated in the onset and progression of the disease. Special emphasis is placed on delivery methods, with a comprehensive comparison of the strengths and weaknesses of each proposed approach. Our hypothesis proposes that employing multiple microRNAs concurrently, with the ability to directly influence BDNF and activate closely associated pathways, may represent the most promising strategy. Regarding vehicles, although the perfect nanoparticle remains elusive, considering the trade-offs, liposomes emerge as the most suitable option.

Fig. 1. A proposal for the therapeutic use of miRNAs in treating major depressive disorder targeting BDNF.

The scheme involves the simultaneous administration, either intravenously or intranasally, of synthetic miRNA molecules designed to target specific endogenous miRNAs that regulate BDNF and its interaction with TrkB (e.g., miR-491-3p), as well as miR-181-3p, which indirectly influences neurotrophin functioning. Both antagonistic and mimic miRNAs are employed. This approach holds the potential to reduce neuroinflammation and enhance neuroplasticity by up-regulating BDNF levels and its activity. BBB blood–brain barrier, BDNF brain-derived neurotrophic factor, TrkB tropomyosin receptor kinase B.

Fig. 2. Schematic view of advantages and major drawbacks of artificial vehicles for miRNA delivery.

Lipid-based nanoparticles (NPs), i.e., liposomes [–107] and exosomes [, –111], offer a high degree of safety, customization, and versatility in terms of encapsulating hydrophilic payloads, including miRNAs. However, they can be susceptible to drug leakage, exhibit relatively shorter half-lives, and face challenges in achieving specific targeting. On the other hand, Polyethyleneimines (PEIs) [, –115] and inorganic materials (i.e., gold and iron oxide NPs) [–121] provide stability and can be engineered for precise targeting, but potential long-term toxicity concerns and limited biodegradability warrant careful consideration. Collectively, inorganic NPs exhibit considerable potential in miRNA therapeutic delivery. Nevertheless, we assert that their limitations surpass their potential advantages, whereas lipid-based carriers show promise owing to their safety profile and customizability, along with the possibility of implementing modifications to mitigate their drawbacks. CNS central nervous system, BBB blood–brain barrier, PEG polyethylene glycol.