The role of ketamine in major depressive disorders: Effects on parvalbumin-positive interneurons in hippocampus.

Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.

VEGF reverts the cognitive impairment induced by a focal traumatic brain injury during the development of rats raised under environmental enrichment.

The role of VEGF in the nervous system is extensive; apart from its angiogenic effect, VEGF has been described as a neuroprotective, neurotrophic and neurogenic molecule. Similar effects have been described for enriched environment (EE). Moreover, both VEGF and EE have been related to improved spatial memory. Our aim was to investigate the neurovascular and cognitive effects of intracerebrally-administered VEGF and enriched environment during the critical period of the rat visual cortex development. Results showed that VEGF infusion as well as enriched environment induced neurovascular and cognitive effects in developing rats. VEGF administration produced an enhancement during the learning process of enriched animals and acted as an angiogenic factor both in primary visual cortex (V1) and dentate gyrus (DG) in order to counteract minipump implantation-induced damage. This fact revealed that DG vascularization is critical for normal learning. In contrast to this enriched environment acted on the neuronal density of the DG and V1 cortex, and results showed learning enhancement only in non-operated rats. In conclusion, VEGF administration only has effects if damage is observed due to injury. Once control values were reached, no further effects appeared, showing a ceiling effect. Our results strongly support that in addition to neurogenesis, vascularization plays a pivotal role for learning and memory.

Effects of VEGF administration or neutralization on the BBB of developing rat brain.

We investigated the effects of exogenous Vascular Endothelial Growth Factor VEGF combined with an enriched environment on BBB integrity after a minimal trauma induced during the first days of the critical visual period in rats, when peak levels of endogenous VEGF secretion are reached. VEGF was administered using osmotic mini-pumps placed in middle cortical layers of P18 Long-Evansrats. Tissue changes were evaluated using conventional histology. BBB integrity was shown by immunohistochemistry techniques for EBA and GluT-1. Mini-pump implantation produced a wider cavity in anti-VEGF infused rats. In VEGF-infused rats there was a damaged region around the cannula that was smaller in rats raised in an enriched environment (EE). The administration of VEGF induced a high concentration of plasma proteins in the neuropil around the point of cannula placement and a high inflammatory reaction. VEGF-infused rats raised in an EE showed a lower degree of extravasation and better tissue preservation. Anti-VEGF administration produced a lower protein expression profile and more widespread deterioration of tissue. Double immunofluorescence for EBA and GluT-1 showed that the administration of VEGF preserves the tissue, which remains present but not fully functional. In contrast, a combination of VEGF administration and an EE partially protects the functionally damaged tissue with a higher preservation of BBB integrity.

The role of eNOS in vascular permeability in ENU-induced gliomas.

Brain edema in gliomas is an epiphenomenon related to blood-brain-barrier (BBB) breakdown in which endothelial nitric oxide synthase (eNOS) plays a key role. When induced by vascular endothelial growth factor (VEGF), eNOS synthesizes nitric oxide that increases vascular permeability. We investigated the relationship between eNOS, VEGF and BBB dysfunction in experimental gliomas.Tumors were produced in Sprague-Dawley rats by transplacentary administration of Ethylnitrosourea (ENU). Immunoexpression of eNOS and VEGF(165) was studied to identify locations of vascular permeability. BBB permeability was evaluated using gadolinium and intravital dyes and BBB integrity by endothelial barrier antigen (EBA), glucose transporter-1 (GluT-1) and occludin immunostaining. Low grade gliomas displayed constitutive eNOS expression in endothelial cells and in VEGF-positive astrocytes surrounding vessels. Malignant gliomas overexpressed eNOS in aberrant vessels and displayed numerous adjacent reactive astrocytes positive for VEGF. Huge dilated vessels inside tumors and glomeruloid vessels on the periphery of the tumor showed strong immunopositivity for eNOS and a lack of occludin and EBA staining in several vascular sections. BBB dysfunction on these aberrant vessels caused increased permeability as shown by Gadolinium contrast enhancement and intravital dye extravasation.These findings support the central role of eNOS in intra- and peritumoral edema in ENU-induced gliomas.