Evaluation of Antidepressant Potential of Test Sample/Formulation in UCMS-Induced Depression
Depression is a complex neuropsychiatric disorder characterized by persistent sadness, anhedonia, cognitive impairment, and altered neurochemical signaling. Increasing evidence suggests that chronic stress, neuroinflammation, oxidative stress, and monoamine imbalance play central roles in its pathophysiology. The present preclinical study was designed to evaluate the antidepressant potential of MITO1 using a Unpredictable Chronic Mild Stress (UCMS)-induced depression model in rats.
Study Design and Animal Grouping
Male Sprague Dawley rats were divided into six groups: normal control, disease control, reference control (Escitalopram 10 mg/kg), and three MITO1-treated groups receiving 30, 90, and 270 mg/kg orally once daily. Depression was induced by exposing animals to a battery of mild stressors applied randomly for 8 weeks, mimicking human chronic stress exposure.
Behavioral Assessment of Depression
Depressive-like behaviors were evaluated on days 0, 28, and 56 using validated behavioral paradigms. The sucrose preference test assessed anhedonia, while the forced swim test and tail suspension test measured behavioral despair through immobility time. Novelty suppressed feeding test was used to evaluate anxiety-related behavior and motivational deficits. Disease control animals exhibited reduced sucrose preference, increased immobility time, and prolonged feeding latency, confirming successful induction of depression.
Neurochemical and Biochemical Analysis
Monoamine neurotransmitters including dopamine, serotonin, norepinephrine, epinephrine, and histamine were quantified in brain tissue using HPLC. UCMS exposure resulted in significant depletion of these neurotransmitters, correlating with behavioral deficits. MITO1 treatment dose-dependently restored monoamine levels, indicating improvement in reward processing, mood regulation, alertness, and stress responsiveness.
Oxidative stress markers such as SOD, catalase, GPx, GSH, and MDH were also assessed. MITO1 significantly enhanced antioxidant defenses, suggesting protection against stress-induced oxidative damage.
Role of Neuroinflammation and Cytokines
Chronic stress elevated pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IFN-γ in brain tissue, while reducing the anti-inflammatory cytokine IL-10. MITO1 treatment markedly suppressed neuroinflammation by downregulating pro-inflammatory cytokines and restoring IL-10 levels, highlighting its immunomodulatory role.
Molecular and Cellular Biomarkers
Expression of inflammatory and microglial activation markers such as NLRP3, Caspase-1, Iba-1, iNOS, CD16, NF-κB, and TLR4 was increased in depressed animals. Conversely, neuroprotective M2 markers including CD206 and Arg-1 were reduced. MITO1 treatment reversed these molecular alterations, promoting a shift from pro-inflammatory M1 microglial activation to a neuroprotective M2 phenotype.
Histopathological Findings
Histopathological examination of the frontal cortex and hippocampus revealed neuronal shrinkage, reduced cortical thickness, synaptic loss, and glial cell depletion in UCMS-exposed rats. MITO1-treated groups showed marked improvement in neuronal architecture, synaptic density, and overall cellular integrity.
What should be the Conclusion?
The findings demonstrate that MITO1 exhibits significant antidepressant-like activity in the UCMS-induced rat model of depression. Its beneficial effects are mediated through restoration of monoamine neurotransmitters, attenuation of oxidative stress, suppression of neuroinflammation, modulation of microglial polarization, and protection of neuronal structure. MITO1 emerges as a promising candidate for further development as a novel antidepressant agent.
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