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). D Show more
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
Numerous hypotheses have been proposed for the pathophysiology of bipolar disorder (BD). This study aimed to evaluate serum neuroserpin (NSP), tissue plasminogen activator (tPA), interleukin-6 (IL-6), Show more
Numerous hypotheses have been proposed for the pathophysiology of bipolar disorder (BD). This study aimed to evaluate serum neuroserpin (NSP), tissue plasminogen activator (tPA), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), high-sensitivity C-reactive protein (hsCRP), and sedimentation levels in patients with BD, based on the inflammatory and fibrinolytic system hypothesis, to understand the etiopathogenesis of BD. The second aim of our study was to determine the risk of developing BD type 1 by examining the relationship between tPA and NSP in patients diagnosed with BD type 1. The study included 80 euthymic outpatients with BD type 1 and 80 healthy controls (HC). Individuals with a Hamilton Depression Rating Scale (HAM-D) score of less than 7 and a Young Mania Rating Scale (YMRS) score of less than 4 who did not show any symptoms of mania, depression, or hypomania for the last 6 months were included in the study. In both groups, serum levels of NSP, tPA, IL-6, BDNF, hsCRP, and sedimentation were measured. Compared to the healthy control group, the NSP and tPA levels were lower in the BD group (p<0.001). We found no linear relationship when we analyzed the relationship between tPA and NSP by excluding other variables. (p: 0.027). These findings suggest that tPA and NSP may serve as potential biomarkers for the euthymic period of BD type 1. These biomarkers may provide guidance in understanding the pathophysiology of bipolar disorder. Show less