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 brain-derived 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.

Figure 1. BDNF and cyclic pentapeptide analogs

Panel A depicts the amino acid primary sequence of brain-derived neurotrophic factor (BDNF). Panel B depicts multiple cyclic pentapeptide agonistic analogs of BDNF that can selectively activate the TrkB tyrosine kinase receptor responsible for the multiple physiological effects of BDNF. Multiple diverse amino acid substitutions (Xxx) can be introduced to the cyclic pentapeptide core to modulate both maximal agonistic potency and neuroprotective capacity [20].(Nle, Norleucine).

Figure 2. Neurotransmitter re-uptake inhibitor anti-depressants

Panel A indicates the chemical structures of multiple forms of selective serotonin re-uptake inhibitors (SSRI: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline). Panel B depicts two selective norepinephrine re-uptake inhibitor chemical structures (SNRI: venlafaxine, duloxetine). Both examples of these classes of compound can directly or indirectly mimic the beneficial effects of coordinated physical activity.

Figure 3. Chemical modulators of steroid hormone receptor activity

Panel A depicts two base-structure non-steroidal A-ring mimetic glucocorticoid receptor agonists. Multiple modifications can be made to these base structures to modulate their pharmacodynamics and receptor efficacy (A-ring mimetic - quinol-4-one [70]: aryl pyrazole [71]). Panel B depicts the chemical structures of two selective non-steroidal selective glucocorticoid receptor agonists (SEGRAs: A 276575 [72]; ZK 209614 [73]). Panel C depicts the chemical structures of two selective mineralocorticoid receptor antagonistic agents.

Figure 4. Energy-regulatory and developmentally-targeted pharmacomimetics of coordinated physical activity

Panel A depicts the chemical structures of two agents that possess exercise pharmacomimetic activity by controlling stress-response pathways. Panel B depicts the diverse chemical structures of pharmacologically active agents that can effectively modulate the Wnt pathway in hippocampal tissue.

Figure 5. Multiple mechanistic routes for current and future hippocampally-targeted pharmacomimetics of exercise

It is clear that amongst the currently studied neurochemical pathways that translate the beneficial actions of coordinated physical activity to neuronal health there are significant points of convergence, e.g. the pharmacological effects of IGF-1 or norepinephrine/serotonin modulation upon BDNF. With furthere research additional functional connections may also arise between the other mechanistic pathways delineated in the figure, thus providing us with additional key loci of exercise pharmacomimesis. It is likely in the future that many more efficacious and tractable pathways will also emerge to allow additional therapeutic compounds to be developed that will potentienally better mimic the beneficial effects if coordinated physical activity.