Brain Adaptation to Stressful Stimuli: A New Perspective on Potential Therapeutic Approaches Based on BDNF and NMDA Receptors

Abstract

A variety of sublethal or stressful stimuli induce a phenomenon in the brain known as tolerance, an adaptive response that protects the brain against the same stress, or against a different stress (cross-tolerance). Understanding the molecular mechanisms of brain preconditioning holds promise in developing innovative therapies to prevent and treat neurodegenerative disorders, particularly ischemic stroke. Many of the detailed steps involved in tolerance and cross-tolerance are unknown. It is also likely that different stressors differentially regulate sets of genes, transcription factors, and signal transduction pathways that depend upon the molecules that are released in response to the stressor, activation of particular receptors, and the surrounding milieu. The focus of this review is to highlight a few examples of stimuli that induce tolerance: 1) cortical spreading depression; 2) 3-nitropropionic acid; and 3) 2-deoxy-D-glucose. We will summarize by discussing one pathway where intracellular mediators may converge to upregulate intrinsic neuronal survival pathways to promote survival by resisting damage. This mechanism, activation of N-methyl-D-aspartate receptors and its integral relationship with brain-derived neurotrophic factor, may be a critical and general mechanism developed in brain to respond to stressful stimuli.

Subchronic Alpha-Linolenic Acid Treatment Enhances Brain Plasticity and Exerts an Antidepressant Effect: A Versatile Potential Therapy for Stroke

“…Our in vitro and in vivo studies show that the expression of BDNF levels was increased after ALA treatment, both in NSC, hippocampal mature neurons and in cortical/hippocampal tissue. BDNF is an immediate early gene that responds rapidly after membrane depolarization, and is involved in the maintenance and support of neurons (Barde, 1994;Marini et al, 2008). It is essential in neuronal survival and behavior-related plasticity (Lipsky and Marini, 2007).…”

Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance

“…3-NPA is an irreversible inhibitor of the mitochondrial protein succinate dehydrogenase (respiratory Complex II), an enzyme complex that participates in both the citric acid cycle and the electron transport chain, catalyzing the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol (Marini et al , 2008). Inhibition of Complex II is associated with increased production of cellular ROS (Mandavilli et al , 2005) and, in models of acute and chronic toxicity, 3-NPA can produce striatal neural damage similar to that observed in Huntington’s disease (Brouillet et al , 2005).…”

Targeting the neurovascular unit for treatment of neurological disorders

“…However, the insulin receptor comparatively is the better candidate for RMT drug delivery with the human insulin mAb (HImAb) being 900% more active and 10 times more effective than any human TfR (Boado et al, 2010; Ulbrich et al, 2010). Successful pre-clinical trials using HImAb include transport of neuroprotective peptides like BDNF, which may have therapeutic benefit in diseases like stroke (Marini et al, 2008), memory disorders (Longo et al, 2007), or depression (Yulug et al, 2009); reintroducing an essential enzyme like tyrosine hydroxylase in PD (Zhang et al, 2003); decoy receptor for TNFβ to reduce neuroinflammation (Zhang et al, 2003); or antibodies to Aβ fibrils to ferry them out of the brain (Boado et al, 2010). The latter being the most novel finding showing the possibility for bidirectional drug transport across the BBB.…”