The rampant abuse of methamphetamine (Meth) and its documented toxicity to brain neurotransmitter systems are well known but its potential damage to other targets such as the brain microvascular endothelium has been overlooked. Moreover, because Meth is highly co-morbid with other health concerns such as stress and post-traumatic stress disorder, it is imperative that the mechanistic underpinnings between stress and Meth are understood so that effective therapeutic strategies can be developed to effectively treat the scope of Meth abuse and overdose. The proposal examines a new consequence associated with the co-morbidity of stress and Meth abuse that is evidenced by long-term damage to the blood-brain barrier (BBB) and brain microvascular endothelium. The long term goal is to identify the comprehensive effects associated with this co-morbidity and assess the risk to human health produced by stress-induced augmentation of brain injury resulting from the abuse of Meth. Our working model provides the basis for the hypothesis that chronic stress-induced neuroinflammation is a contributory factor to the BBB damage observed after Meth exposure and that this damage is manifested as large molecule extravasation into the brain parenchyma and phosphorylation-dependent decreases in endothelial tight junction proteins. The translational rationale is to develop a novel and feasible neuroprotective strategy that targets neuroinflammation and is either prophylactic or can rescue the BBB from the harmful consequences resulting from the combined exposures to stress and Meth. Three distinct but complementary aims will address our hypothesis.
Specific Aim 1 will identify the duration and degree of BBB permeability after the serial exposure to chronic stress and the self administration of Meth.
Specific Aim 2 will examine the underlying causes of BBB permeability and will elucidate the time-dependent neuroinflammatory mechanisms responsible for the permeability changes.
Specific Aim 3 will determine the consequences of the increased permeability of the BBB produced by the serial exposure to stress and Meth by examining the augmentation of neuroinflammation caused by entrance of the oral bacterium associated with "Meth mouth", p. gingivalis, into the brain. The findings will have an overall positive impact because the determination of the causes and consequences of a breach in the BBB can guide the design of future therapeutic strategies for the treatment of METH neurotoxicity and overdose. The hope is to fundamentally advance the field of drug abuse-induced brain injury in general, by broadening the significance of Meth toxicity to include the long-term impact on the cerebral vasculature endothelium and thereby begin to understand the far reaching neurobiological consequences associated with this effect.
The proposal is relevant to public health because methamphetamine is a drug that is abused world-wide and is associated with neurological markers of damage in the human brain. The proposed studies will examine how the frequently observed co-morbidity of stress and Meth exposure can produce inflammatory damage to the blood-brain barrier, an important regulatory component of the brain that also protects the brain from blood-borne toxins. This project is relevant to NIDA's mission because it proposes to describe and delineate the role of inflammation in the damage to the blood-brain barrier that in turn, can provide the basis for the design of a therapeutic strategy that mitigates and rescues the brain from the neurotoxic effects of methamphetamine and stress.
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