Therapeutical Potentials of Protein Kinase C Activators as Antidementic and Cognition-Enhancing Agents

Among the molecular signaling pathways, protein kinase C (PKC) isozymes play a critical role in various types of learning and memory. Abnormal functions of PKC signal cascades in neurons have also been found to represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and other types of memory deficits, including those related to cerebral ischemic/stroke events. In preclinical studies, an inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes results in an enhancement of learning and memory and/or producing antidementic effects. PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity, including neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas, but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognition-enhancing agents and therapeutics against memory loss in the future.

Keywords: Alzheimer's disease, antidementic, bryostatins, cognition, dementia, cerebral ischemia, learning and memory, protein kinase C, stroke, synapses