Pharmacological activation of protein kinase A improves memory loss and neuropathological changes in a mouse model of dementia of Alzheimer's type.
The study investigates the therapeutic potential of the protein kinase A (PKA) activator forskolin in cognitive deficits of mice. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v.)] was used to induce memory deficits in mice, whereas aged mice served as natural model of dementia. Forskolin (2.5, 5, and 10 mg/kg/day, oral) treatment was administered to i.c.v. STZ-treated and aged mice for 14 days. The Morris Water Maze test was used to evaluate learning and memory. Estimation of brain acetylcholinesterase (AChE) activity, brain glutathione, thiobarbituric acid-reactive species, brain myeloperoxidase levels, and histopathological studies were also performed. Both STZ i.c.v. and aging resulted in a marked decline in Morris Water Maze performance, reflecting impairment of learning and memory. STZ i.c.v.-treated mice and aged mice showed a marked accentuation of AChE activity, thiobarbituric acid-reactive species and myeloperoxidase levels along with a decrease in the glutathione level. Further, the stained micrographs of STZ-treated mice and aged mice indicated pathological changes, severe neutrophilic infiltration, and amyloid deposition. Forskolin treatment significantly attenuated STZ-induced and age-related memory deficits, and biochemical and histopathological alterations. The findings indicate that the PKA activator forskolin probably alleviated memory deficits by virtue of its anticholinesterase, antiamyloid, antioxidative, and anti-inflammatory effects. It is concluded that PKA could be explored as a potential therapeutic target in dementia.
aCNS and CVS Research Lab, Faculty of Medicine, Department of Pharmaceutical Sciences and Drug Research, Pharmacology Division, Punjabi University Patiala bDepartment of Pharmaceutical Sciences and Drug Research, Pharmacology Division, Faculty of Medicine, Punjabi University, Patiala, Punjab, India.
Amit
A
Kumar
Nirmal
N
Singh
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005576:Colforsin / Q000008:administration & dosage / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D003704:Dementia / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D013311:Streptozocin
D002800:Cholinesterase Inhibitors; D005576:Colforsin; D013311:Streptozocin; D017868:Cyclic AMP-Dependent Protein Kinases; D000110:Acetylcholinesterase; D005978:Glutathione