Methamphetamine (MA) use is associated with accelerated progression of HIV-associated neurocognitive disorders (HAND), through poorly understood mechanisms. In addition to its well studied ability to induce oxidative stress and glial activation, MA abuse also has pronounced neurovascular effects that are reflected by an increased risk of stroke, persistent white matter hyperintensities and reductions in cerebral blood flow (CBF) in MA abusers. Consistent with this, our preliminary data show that acute MA exposure results in a significant decline in CBF in wild-type mice, as measured by laser doppler flowmetry. Thus, our central hypothesis is that: MA disrupts cerebral blood flow and elicits cerebrovascular changes that exacerbate the progression of HIV-induced neurologic disease. This hypothesis will be tested through three aims.
In Aim 1, we will analyze MA's effects on cerebral blood flow. We will first test whether the effects of acute MA exposure on CBF are exacerbated in animals with underlying HIV-induced neuroinflammatory disease (using gp120 and Tat transgenic mice). We will then probe the underlying mechanism by testing whether MA-induced hypoperfusion is due to the induction of specific vasoactive eicosanoids, and in Aim 1C, we will determine whether chronic MA exposure elicits a sustained reduction in CBF in wild-type mice or in animals with underlying HIV-induced neuroinflammatory disease.
Aim 2 will analyze MA's effects, alone and in combination with HIV virotoxins, on tissue microcirculation and oxygenation, and neuronal metabolism.
In Aim 2 A, we will test whether MA's effects on CBF are accompanied by impairment of regional microcirculation, as measured by radiotracer imaging, and by induction of hypoxic gene expression signatures (Aim 2B).
In Aim 2 C, we will determine whether MA exposure results in impairment of local tissue oxygenation, or changes in local neuronal oxidative metabolism, by using a highly innovative approach (in vivo two-photon nicotinamide adenine dinucleotide [NADH] imaging). Finally, in Aim 3, we will analyze MA's effects on the blood-brain barrier (BBB). HIV virotoxins and acute high-dose MA exposures have been shown to independently damage the BBB, and we will therefore test whether acute exposure to MA results in exacerbated damage to the BBB and induction of microhemorrhages in mice with underlying HIV-induced neuroinflammatory disease, as compared to wild- type mice. This will be assessed by measuring the entry of plasma proteins into the CNS and by the induction of inflammatory vascular changes. Analogous experiments will also be performed in mice with chronic exposure to MA, to determine if this results in prolonged disruption of the BBB. Results from all three aims will be correlated, to determine whether BBB disruption and microhemorrhages are associated with sustained hypoperfusion and reductions in microcirculation. Collectively, these experiments will provide new insight into the mechanisms by which MA accelerates the progression of HAND.

Public Health Relevance

Methamphetamine (MA) abuse has been linked to a worsening of neurologic disease in persons infected with the Human Immunodeficiency Virus type-1 (HIV-1). This proposal seeks to determine whether exposure to MA causes impairment of normal blood flow to the brain, including the development of microhemorrhages (mini-strokes), and whether this is exacerbated in the context of underlying brain inflammation due to HIV. The long-term goal is to understand better how MA exposure worsens neuroAIDS, and to define new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026325-05
Application #
8268548
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Frankenheim, Jerry
Project Start
2008-09-30
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$373,275
Indirect Cost
$130,047
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Silva, Jharon N; Polesskaya, Oksana; Wei, Helen S et al. (2014) Chronic central nervous system expression of HIV-1 Tat leads to accelerated rarefaction of neocortical capillaries and loss of red blood cell velocity heterogeneity. Microcirculation 21:664-76
Polesskaya, Oksana; Sun, Anita; Salahura, Gheorghe et al. (2012) Detection of microregional hypoxia in mouse cerebral cortex by two-photon imaging of endogenous NADH fluorescence. J Vis Exp :
Polesskaya, Oksana; Silva, Jharon; Sanfilippo, Christine et al. (2011) Methamphetamine causes sustained depression in cerebral blood flow. Brain Res 1373:91-100
Gelbard, Harris A; Dewhurst, Stephen; Maggirwar, Sanjay B et al. (2010) Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: a therapeutic strategy based on modulation of mixed lineage kinase. Neurotherapeutics 7:392-8