Purpose: Neurogenic lower urinary tract dysfunction (nLUTD) develops in nearly all patients after spinal cord injury (SCI). Evolving neuroinflammation is considered a key driver of secondary injury and is associated with worsening outcomes. However, few studies have examined treatments for nLUTD after SCI that specifically target these processes. This study investigated whether early montelukast therapy targeting proinflammatory leukotrienes improves long-term urological function and reduces pathological bladder remodeling.Methods: Female Lewis rats received a permanently implanted urinary catheter and underwent contusion SCI (Th8/Th9) or sham surgery. Daily montelukast treatment began 1 day after injury and continued throughout the 2- or 6-month follow-up period. Injury severity and regeneration were evaluated using the Basso-Beattie-Bresnahan locomotor score and microcomputed tomography of the spinal cord. Bladder function was assessed through weekly urodynamic recordings in awake animals, and bladder structure was assessed by histological measurement of wall thickness. Transcriptomic and proteomic analyses were used to characterize the molecular processes underlying bladder remodeling.Results: Spinal cord tissue damage and functional impairment were comparable across animals, regardless of treatment. Montelukast did not improve urodynamic outcomes and was associated with transiently poorer functional scores during early recovery. Bladder wall thickness increased after SCI and was greatest in the treated groups, suggesting ongoing remodeling. Transcriptomic and proteomic analyses demonstrated marked activation of immune and contractility-related pathways in treated animals at 2 months. Animals followed for the longer period showed intensified immune signaling, indicating sustained inflammatory activity.Conclusions: Early montelukast treatment did not improve functional or structural urological outcomes after contusion SCI. The unfavorable functional trends and intensified inflammatory and injury-related pathways suggested adverse effects rather than therapeutic benefit under the conditions studied. These findings may indicate the importance of injury model-specific mechanisms and of dose and timing when developing anti-inflammatory strategies for SCI-induced nLUTD.
Purpose: Serotonin (5-HT) release in the hippocampus is modulated by N-methyl-D-aspartate (NMDA) receptor activity, particularly under hypoxic conditions, but the roles of other neurotransmitter systems remain unclear. This study examined how several neurotransmitters affect spontaneous 5-HT release in rat hippocampal slices and whether these effects are direct or interneuron-mediated.Methods: Rat hippocampal slices (400 μm) were preloaded with [3H]5-HT and superfused with oxygenated buffer. Acetylcholine (ACh), norepinephrine (NE), dopamine (DA), NMDA, γ-aminobutyric acid (GABA), glycine, or neuropeptide Y (NPY) were applied for 20 minutes, and [3H]5-HT release was measured in 10-minute fractions. Tetrodotoxin (TTX) was used in parallel experiments to block action potential-dependent neurotransmission.Results: In control slices, spontaneous [3H]5-HT release reached a stable baseline after approximately 50 minutes of superfusion. ACh (10-5M), GABA (10-5M), glycine (10-5M), and NPY (10-6M) did not significantly affect 5-HT release relative to control. In contrast, NE (10-5M) and DA (10-5M) significantly increased 5-HT release (peaking at ~15%–37% above baseline, P<0.05), and these effects persisted in the presence of TTX, suggesting a direct action on serotonergic terminals. NMDA (10-4M) also transiently enhanced 5-HT release (~22% above baseline, P<0.05), but this effect was completely abolished by TTX, indicating reliance on interneuronal activity.Conclusions: Hippocampal 5-HT release is differentially regulated by neurotransmitter systems: NE and DA act directly at serotonergic terminals, whereas NMDA’s effect requires interneuronal activity. These findings highlight complex neurochemical interactions that may underlie serotonergic modulation in neuropsychiatric disorders.
