👤 Vichuda Charoensaensuk

Coenzyme Q10 (CoQ10) is an endogenous lipid-soluble molecule with antioxidative and anti-inflammatory properties. Chronic environmental stress can induce neuroinflammation, leading to posttraumatic stress disorder (PTSD)-like behaviors and cognitive deficits. However, therapeutic options that achieve high efficacy with minimal adverse effects remain limited. Here, we investigated the effects of ubiquinol, the reduced form of CoQ10, administered via oral mucosal absorption on behavioral and molecular changes in mice subjected to social disruption (SD). Our results showed ubiquinol administration ameliorated SD-induced social avoidance and anxiety-like behaviors, accompanied by increased hippocampal brain-derived neurotrophic factor (BDNF) and decreased monoamine oxidases A and B (MAO-A and MAO-B). Additionally, ubiquinol suppressed SD-induced upregulation of inducible nitric oxide synthase (iNOS), lipocalin 2, and interleukin-6 (IL-6) in the hippocampus. In microglial cells, CoQ10 effectively attenuated lipopolysaccharide (LPS)-induced increases in iNOS and lipocalin 2 as well. Notably, CoQ10 restored the downregulated expression of peroxisome proliferator-activated receptor alpha (PPARα) observed under SD mice and microglial cells stimulated by LPS. The protective effects of ubiquinol were abrogated by inhibiting PPARα, resulting in reduced BDNF and elevated MAOs and pro-inflammatory mediators. Collectively, these findings demonstrate that ubiquinol mitigates neuroinflammation and behavioral impairments through PPARα-dependent mechanisms, thereby promoting BDNF expression and suppressing upregulation of monoamine oxidases in the hippocampus. The current study provides mechanistic insight into the potential therapeutic application of CoQ10 for chronic stress-induced behavioral and cognitive deficits. Show less

Lumbrokinase belongs to a group of fibrinolytic enzymes, particularly tissue plasminogen activator (tPA), which can facilitate the proteolytic maturation of brain-derived neurotrophic factor (BDNF). Drugs administered via oral or intravenous routes are often metabolized in the liver or kidneys, and these delivery methods for brain-targeted therapies must overcome the natural barriers of the central nervous system (CNS). Intranasal drug delivery via the nose-to-brain route has emerged as a promising approach to bypass these barriers, enhance drug penetration into the brain, and minimize exposure to peripheral organs. In this study, we demonstrate that intranasally administered lumbrokinase successfully reached the brain. Behaviorally, lumbrokinase significantly improved chronic social defeat stress (CSDS)-induced social avoidance and cognitive impairments. At the molecular level, CSDS increased hippocampal precursor BDNF (proBDNF) expression and reduced mature BDNF (mBDNF) compared with control mice. Importantly, lumbrokinase treatment promoted the expression of tPA and plasmin, thereby restoring the proBDNF/mBDNF balance in the hippocampus and reversing stress-induced maladaptive behaviors. Additionally, lumbrokinase increased TrkB, PSD95, and enhanced phosphorylation of PI3K, AKT, and mTOR in the hippocampus, indicating improved synaptic signaling and plasticity. In conclusion, this study demonstrates that intranasal delivery enables lumbrokinase to reach the brain effectively, providing robust therapeutic benefits against CSDS-induced behavioral and cognitive deficits. Enhancing plasmin-mediated BDNF maturation through non-invasive intranasal enzyme delivery may represent a promising approach for treating stress-related mood disorders. Show less