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Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats
Adriana Fernanda Kuckartz Vizuete1,2,3,4, Ana Paula Moreira5,6, Lisandra Eda Fusinato Zin5,6
1Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil. adriana.vizuete@ufcspa.edu.br.
Metformin treatment, whether early or late, improved cognitive function and reduced neuroinflammation in a rodent model of Alzheimer's disease (AD). This suggests metformin's potential neuroprotective benefits for dementia, especially in conditions like type 2 diabetes mellitus (T2DM).
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Alzheimer's disease (AD) is the primary cause of dementia, posing significant societal and economic burdens.
- Risk factors for sporadic AD include advanced age and type 2 diabetes mellitus (T2DM).
- Metformin, a first-line T2DM drug, exhibits peripheral and central nervous system effects, but its neuroprotective mechanisms remain unclear.
Purpose of the Study:
- To investigate the optimal timing for initiating metformin treatment in a sporadic Alzheimer's disease (AD)-like rodent model.
- To evaluate the neuroprotective effects of early versus late metformin administration on cognitive function and neuroinflammation.
Main Methods:
- A sporadic AD-like dementia model was induced in rats via intracerebroventricular streptozotocin (STZ) administration.
- Two metformin treatment protocols were employed: early (2 days post-STZ) and late (20 weeks post-STZ), both at 50 mg/Kg/daily for 28 days.
- Cognitive behavior was assessed using novel object recognition and Morris's water maze tasks; neuroinflammatory markers (TLR4, RAGE, TNF-α, NF-κB) and the methylglyoxal/RAGE/NOX-2 pathway were analyzed.
Main Results:
- Both early and late metformin treatments significantly improved cognitive performance in STZ-induced rats.
- Metformin administration reduced key neuroinflammatory markers, including TLR4, RAGE, TNF-α, and NF-κB protein expression.
- Metformin treatment restored glyoxalase 1 activity and GSH levels, downregulating the methylglyoxal/RAGE/NOX-2 signaling pathway.
Conclusions:
- Both early and late metformin administration demonstrate neuroprotective effects in an STZ-induced dementia model.
- Metformin mitigates neuroinflammation and oxidative stress implicated in Alzheimer's disease pathogenesis.
- These findings highlight metformin's potential therapeutic role in managing dementia, particularly in the context of insulin resistance and diabetic encephalopathy.
