Pharmacomimetics of Exercise: Novel Approaches for Hippocampally- Targeted Neuroprotective Agents

Abstract

Coordinated and constructive physical activity is correlated with the maintenance of cognitive function in humans. Voluntary running also enhances neuroplasticity in adult and aging rodents, but the molecular pathways underlying these effects are still being elucidated. Considering the multifactorial nature of the biochemical links between physical activity and neurophysiology it is likely that there are many pharmacological mechanisms by which the beneficial actions of exercise can be effectively reproduced using chemical agents. Most studies to date have focused on brainderived neurotrophic factor (BDNF) as a signaling target for the enhancement of neuronal function by exercise. The goal of the current review is to move beyond BDNF by exploring the diversity of molecular pathways regulated by physical activity in a variety of situations. We will discuss the availability and mechanism of action for several diverse physical activity pharmacomimetics. As physical activity enhances both neuroplasticity and cognition, understanding the molecular targets for these effects may lead to the development of protent new therapeutic interventions for age-related neurodegenerative conditions such as Alzheimer's disease.

Enhancing Hippocampal Neuronal Numbers in Morphine-Dependent Rats by Voluntary Exercise Through a Brain-Derived Neurotrophic Factor-Mediated Mechanism

“…Voluntary exercise restored both the capacity of neuronal counting and the performances in the water maze test. Our finding is consistent with previous results showing that exercise enhances learning and memory capability through stimulating hippocampal neurogenesis leading to enhance learning and memory capability (9,10,12,14,18,23,24).…”

“…In line with our study, it was shown that the hippocampal DG (as a source of neural stem cells) continues to generate new neurons throughout the lifespan, and physical activity also causes an increase in neurogenesis in the DG of the hippocampus, a brain area important for learning, memory (10), and synaptic plasticity (17). Our finding is consistent with previous results showing that exerciseassociated changes in synaptic plasticity occurred in the same region where neurogenesis occurred by running, suggesting that newborn cells have a functional role in this process (9).…”

“…In line with our study, it was shown that BDNF action via the TrkB receptor is an important mediator between exercise and neural functions such as synaptic plasticity, neurogenesis, learning, and memory (7,(9)(10)(11)(12)(13)(14)25). The effects of exercise on behavioral and synaptic function are qualitatively similar to those of BDNF application (10).…”

“…The effects of exercise on behavioral and synaptic function are qualitatively similar to those of BDNF application (10).…”

“…Attenuation of adult neurogenesis interferes with learning of a hippocampus-dependent task and expression of long-term potentiation (LTP) in vitro (1,5), and increases a vulnerability to anxiety-like behaviors (6). In human subjects and in rodents, voluntary or forced exercises promote neurogenesis in the adult dentate gyrus (DG) (7) and brain-derived neurotrophic factor (BDNF) might have a potential role in exercise-induced neurogenesis, synaptic plasticity, and memory through its actions on the tyrosine kinase B (TrkB) receptor (8)(9)(10)(11)(12)(13)(14). We have recently demonstrated that voluntary exercise diminishes the severity of morphine dependency (15) and the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats (16), enhances LTP in hippocampal DG area (17), and ameliorates the spatial memory deficits in morphine-dependent rats through TrkB receptor of BDNF (15).…”