Abstract
To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus accumbens. Behaviorally, these include feelings of worthlessness, anxiety, dread of the future, and significant reductions in the capacity to anticipate and experience pleasure. Physiologically, these include activation of the CRH and noradrenergic system in brain and the sympathetic nervous system and hypothalamic–pituitary–adrenal axis in the periphery. Patients with depression are also insulin-resistant. The PPARg system influences each of these behavioral and physiological in ways that would ameliorate the manifestations of depressive illness. In addition to the cognitive and behavioral manifestations of depression, depressive illness is associated with the premature onsets of coronary artery disease, stroke, diabetes, and osteoporosis. As a consequence, patients with depressive illness lose approximately seven years of life. Inflammation and insulin resistance are two of the predominant processes that set into motion these somatic manifestations. PPARg agonists significantly ameliorate both pathological processes. In summary, PPARg augmentation can impact positively on multiple significant pathological processes in depression. These include loss of brain tissue, defective neuroplasticity and neurogenesis, widespread inflammation in the central nervous system and periphery, and insulin resistance. Thus, PPARg agonists could potentially have significant antidepressant effects.
Highlights
The World Health Organization ranks depression as the second greatest cause of disability worldwide
Among the key regulators of the stress response in the brain and periphery is the peroxisome proliferator activated receptor gamma (PPARg) system, which I postulate plays a major role in depression, especially in one of the most pronounced concomitants of depression, namely central and peripheral inflammation [12]
I will provide an overview of the biological changes associated with depression, with particular emphasis on the extensive roles of the PPARg system in depressive illness
Summary
The World Health Organization ranks depression as the second greatest cause of disability worldwide. As examples of the activation of the stress response, we first noted that both CSF and plasma norepinephrine and epinephrine are elevated around the clock in drug-free patients with melancholia in hourly samples taken for 30 consecutive hours (Figure 1). Both compounds are arousal-producing and anxiogenic in brain and transduce multiple autonomic and metabolic aspects of the stress response [8,10,20]. PPARg agonists are potent stimuli to both neuroplasticity and neurogenesis, which, I will show, are both markedly decreased in depression [12]
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