ensayos

Salud Mental 2011;34:497-506 Fármacos antidepresivos: reguladores de la neurogénesis hipocámpica

Los fármacos antidepresivos como reguladores
de la neurogénesis hipocámpica de roedores
y humanos adultos
Gerardo Ramírez-Rodríguez,1 José Laguna-Chimal,1 Nelly M. Vega-Rivera,2 Leonardo Ortiz-López,1
Luis Méndez-Cuesta,1 Erika M. Estrada-Camarena,2 Harish Babu3
Artículo original

SUMMARYNew neuron formation in the adult brain extends our knowledge and
incorporates a novel dimension about brain plasticity. Adult neurogenesis is a complex process regulated by different factors within the
niche, where adult neural stem cells reside, proliferate and
differentiate. Neural stem cell together with astrocytes and endothelial
cells form the principle components of this complex niche.Other
molecular factors that regulate adult neurogenesis are the neurotransmitters (GABA, glutamate, serotonin, dopamine); hormones
(prolactin, growth hormone, estrogens and melatonin); growth factors
(FGF, EGF, VEGF) and neurotrophins (BDNF, NT3). All of them regulate
different aspects of the neurogenic process.
Behavioral regulators that influence new neuron formation in
the adult braininclude physical activity, complex stimulatory
environment best known as enrichment environment, and social
interaction. Voluntary physical activity with free access to the running
wheel increases the number of proliferating cells, while the complex
stimulatory environment provided by enriched environment
preferentially influences survival of newborn cells. In addition, social
interactionhas a positive influence on the new neuron formation in
the dentate gyrus (DG).
Although adult hippocampal neurogenesis is positively regulated
by the aforementioned factors, there are different conditions with
negative influence on this process. Some of these conditions are stress
exposure and sleep deprivation. Both conditions are present in
neuropsychiatric diseases such as depression,anxiety and
schizophrenia. Thus, stress and sleep deprivation impair adult
hippocampal neurogenesis.
Alteration of the neurogenic process following stress occurs due
to the high levels of glucocorticoid receptors within the hippocampus
and because exposure to stress causes the increase in glucocorticoid
levels.
Preclinical studies have shown that exposure to different classes
of stressorsaffect hippocampal neurogenesis. Prolonged exposure
to stressors (chronic mild stress), predatory odor, foot shock, acute
force swimming and psychosocial stress not only affect mature
neuronal plasticity but also hippocampal neurogenesis.

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Although there is information about the effects of stress on adult
neurogenesis, the mechanism by which stress causes inhibition ofhippocampal neurogenesis remains unclear. Recent work showed
that exposure to stress increases the pro-inflammatory cytokine
interleukin-1β (IL-1β) in several brain areas. Also, administration of
IL-1β exerts stress-like effects including down-regulation of
hippocampal brain derived neurotrophic factor (BDNF). Additionally,
inhibition of the receptor for IL-1β prevents stress-like effects.
Moreover,the suppression of cell proliferation is mediated by direct
actions of IL-1β on IL-1RI receptors localized on precursor cells. These
findings support that IL-1β is a critical mediator of the antineurogenic
effect caused by acute and chronic stress. However, IL-1β is not the
unique mediator of stress that could be involved in the alteration of
adult hippocampal neurogenesis. Recently it wasreported that the
decrease in cell proliferation concomitantly occurs with an increase
of IL6 and TNFα levels.
Preclinical studies have suggested that adult hippocampal
neurogenesis is not a sole cause of depression or the sole mechanism
of treatment efficacy, but it is likely an important contributor to this
complex disorder. In order to revert the effects of stress on adult
hippocampal...