Ampakines May Reverse Age-Related Memory Loss

A new therapy may reverse age-related cognitive decline, even after the drug has left the body, according to researchers from the University of California, Irvine (UC Irvine). Ampakines, agents that have been shown to enhance memory, appear to trigger endogenous brain-derived neurotrophic factor (BDNF), a natural mechanism in the brain that could restore neuronal viability and synaptic plasticity through increased trophic support.

Because previous studies have demonstrated that hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) occur in middle-aged adults, the UC Irvine team, lead by Christine Gall, PhD, professor of anatomy and neurobiology, and Gary Lynch, PhD, professor of neuroscience, focused their study on middle-aged rats. Two groups of rats were treated in vivo twice a day for 8 days; one group received an ampakine, the other received placebo. In the first 4 days, the ampakine-treated rats received injections of saline plus 15% to 20% 2-hydroxypropyl-beta-cyclodextrin. In the next 4 days, they received injections of 5 mg/kg of ampakine CX929, a proprietary compound from Cortex Pharmaceuticals (Irvine, California). When the rats' brains were examined using electrophysiology and protein measures, they showed increased BDNF protein levels in the cortical telencephalon and restored stabilization of basal dendritic LTP.

The results of the study suggest that even brief exposure to ampakines can elevate endogenous BDNF protein levels. Restoration of LTP was found in the rats more than 18 hours after the ampakine had cleared from the animals' bodies. This was significant, according to the authors, because the therapy has a half-life of only 15 minutes. Therefore, they concluded that daily ampakine treatments might have enduring effects.

According to the authors of the study, the results also suggest that neurotrophin levels in the adult brain can be regulated in a way that is minimally disruptive to physiology and behavior. The authors hope that therapies using ampakines may eventually be used to treat age-related memory impairment as well as CNS disorders such as Alzheimer disease and schizophrenia.

The citation for this study is Rex CS, Lauterborn JC, Lin CY, et al. Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor. J Neurophysiol. 2006;96:677-685.