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4-aminopyridine exerts anxiolytic and pro-cognitive effects in mice model of medial prefrontal cortex ischemia
Esmaeil Imani-Almas1,2, Javad Mahmoudi2, Mehdi Farhoudi2
1Department of Neuroscience, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract:
Brain ischemia is a major global cause of disability, frequently leading to psychoneurological issues. This study investigates the effects of 4-aminopyridine (4-AP) on anxiety, cognitive impairment, and potential underlying mechanisms in a mouse model of medial prefrontal cortex (mPFC) ischemia. Mice with mPFC ischemia were treated with normal saline (NS) or different doses of 4-AP (250, 500, and 1000 µg/kg) for 14 consecutive days. The open field test, elevated plus maze, Barnes maze, and novel object recognition test were used to perform a series of behavioral assessments to evaluate anxiety as well as spatial and episodic memory. Serum corticosterone levels and changes in oxidative stress markers (MDA, SOD, GPx, and TAC) were measured by ELISA. Inflammatory and apoptotic markers (p-P38, NF-κB, IL-1β, TNF-α, p-PI3K, p-AKT, Caspase-3, BAX, and BCL2) were analyzed via western blotting. Results showed that mPFC ischemia induced anxiety-like behavior and disrupted both recognition and spatial memory at the behavioral level. Additionally, ischemia increased serum corticosterone levels, elevated oxidative stress, and upregulated inflammatory and apoptotic markers. However, 4-AP at the highest dose significantly mitigated these behavioral and molecular deficits. These findings suggest that 4-AP alleviates anxiety-like behavior and cognitive impairment associated with mPFC ischemia, possibly through modulation of corticosterone, oxidative stress, inflammation, and apoptotic signaling pathways.
Insights
4-aminopyridine (4-AP) treatment significantly improved anxiety and memory deficits in a mouse model of brain ischemia. This suggests 4-AP may offer therapeutic potential for psychoneurological issues following brain injury.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Brain ischemia is a leading cause of global disability, often resulting in psychoneurological problems.
- Medial prefrontal cortex (mPFC) ischemia is a specific type of brain injury impacting cognitive and emotional functions.
- Understanding the molecular mechanisms behind these deficits is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the therapeutic effects of 4-aminopyridine (4-AP) on anxiety and cognitive impairment in a mouse model of mPFC ischemia.
- To explore the underlying mechanisms, including the modulation of stress hormones, oxidative stress, inflammation, and apoptosis.
Main Methods:
- Mice with mPFC ischemia were treated with varying doses of 4-AP or saline for 14 days.
- Behavioral tests (open field, elevated plus maze, Barnes maze, novel object recognition) assessed anxiety and memory.
- Biochemical analyses (ELISA, Western blotting) measured serum corticosterone, oxidative stress markers, and inflammatory/apoptotic markers.
Main Results:
- mPFC ischemia induced anxiety-like behaviors and impaired spatial and recognition memory.
- Ischemia elevated serum corticosterone, increased oxidative stress, and upregulated inflammatory and apoptotic markers.
- The highest dose of 4-AP significantly reversed these behavioral and molecular changes.
Conclusions:
- 4-aminopyridine demonstrates significant potential in alleviating anxiety and cognitive deficits caused by mPFC ischemia.
- The therapeutic effects of 4-AP may be mediated by its ability to modulate corticosterone levels, oxidative stress, inflammation, and apoptosis.
