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AIM The aim of the present work was to explore the outcome of combination of Calcineurin (CaN) inhibitor and Protein Kinase A (PKA) activator, in mouse models of experimental dementia. METHODS Cognitive deficits were induced in mice by injecting Streptozotocin (STZ) intracerebroventricularly (i.c.v.); on the other hand aged animals were procured as a natural model of dementia. To assess cognitive function of mice Morris water maze (MWM) test was utilized; various biochemical studies and histopathological studies were also carried out. RESULTS STZ injection and aging resulted in significant development of cognitive deficits; along-with enhancement of Myeloperoxidase (MPO) levels, Thiobarbituric Acid Reactive Species (TBARS), Acetylcholinestrase (AChE) activity, and reduced Glutathione (GSH) levels. Histopathological studies demonstrated pathological changes such as amyloid deposition and severe neutrophilic infiltration in brains of these mice. Donepezil /combination of Tacrolimus and Forskolin treatment markedly improve cognitive function, biochemical parameters, and histopathological alterations in STZ treated and aged mice. CONCLUSION The outcome reveals that combination of CaN inhibitor and PKA activator has significantly alleviated memory dysfunction, biochemical alteration and histopathological changes quiet comparable to Donepezil. It has been inferred that combination of CaN and PKA can be served as an important target in dementia.