Methamphetamine and 3, 4- methylenedioxymethamphetamine (MDMA) are two most common club drugs, and are very popular among younger generation. These illicit substances are used by millions of people every year and their use is more popular among gay population. Both methamphetamine and MDMA are known to cause neurotoxicity including changes in structure of the brain, especially in the areas associated with depression and cognitive problems. There is indirect evidence that Methamphetamine and MDMA might affect course of the disease among HIV-1 positive drug-users as evident by higher incidence of HIV-1 infection and increased viral load and as well as neuroinflammation among drug users. Role of dopamine (DA), dopamine transporter (DT), tyrosine hydroxylase (TH) and oxidative stress markers is well established in methamphetamine and MDMA-mediated neurotoxicity. However role of cytokine and chemokine remains under explored. On the other hand HIV is known to cause HIV-associated dementia (HAD) and illicit substances especially opiates have been documented to compound these effects. Two HIV proteins (Tat and gp120) have been studied in great detail for their ability to induce HAD. However, viral Vpr and Nef, though implicated, but not very well studied for their role in HAD. Furthermore, there is only limited information available regarding possible synergy between methamphetamine and MDMA on one hand and different virotoxins on the other. In this proposal we will determine role of cytokines and chemokine in methamphetamine and MDMA-mediated neurotoxicity and find out whether concurrent use of 2 drugs increases neurotoxicity. We will determine role of HIV Vpr and Nef in neurotoxicity which has been relatively unexplored. We will also determine whether there is synergy between illicit drugs and virotoxins and whether neurotoxic effect can be abrogated by use of antagonist and siRNA. These in vitro findings will be extended to in vivo experiments wherein combined effect of methamphetamine or MDMA and virotoxins will be explored in HIV Tat, Nef and gp120 transgenic mice.

Public Health Relevance

This application proposes to dissect role of the cytokine(s) and chemokine(s) in methamphetamine and MDMA-mediated neurotoxicity. Experiments are also planned to elucidate the role of viral proteins (HIV Vpr and Nef) in HAD, and whether there is synergy between club drugs and virotoxins for their ability to induce neurotoxicity. We will also test pharmacological inhibitors and viral siRNA for their potential to abrogate neurotoxicity. In vitro results will be extended to a model system using transgenic mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025528-04
Application #
8254416
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Lawrence, Diane M
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$286,169
Indirect Cost
$94,109
Name
University of Missouri Kansas City
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Jackson, Austin R; Shah, Ankit; Kumar, Anil (2014) Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One 9:e109603
Liu, Xun; Shah, Ankit; Gangwani, Mohitkumar R et al. (2014) HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors. Sci Rep 4:4450
Earla, Ravinder; Kumar, Santosh; Wang, Lei et al. (2014) Enhanced methamphetamine metabolism in rhesus macaque as compared with human: an analysis using a novel method of liquid chromatography with tandem mass spectrometry, kinetic study, and substrate docking. Drug Metab Dispos 42:2097-108
Shah, A; Kumar, S; Simon, S D et al. (2013) HIV gp120- and methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1. Cell Death Dis 4:e850
Shah, Ankit; Silverstein, Peter S; Singh, Dhirendra P et al. (2012) Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF-?B pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes. J Neuroinflammation 9:52
Liu, Xun; Silverstein, Peter S; Singh, Vijeta et al. (2012) Methamphetamine increases LPS-mediated expression of IL-8, TNF-* and IL-1* in human macrophages through common signaling pathways. PLoS One 7:e33822
Silverstein, Peter S; Shah, Ankit; Gupte, Raeesa et al. (2011) Methamphetamine toxicity and its implications during HIV-1 infection. J Neurovirol 17:401-15
Shah, Ankit; Singh, Dhirendra P; Buch, Shilpa et al. (2011) HIV-1 envelope protein gp120 up regulates CCL5 production in astrocytes which can be circumvented by inhibitors of NF-?B pathway. Biochem Biophys Res Commun 414:112-7
Shah, Ankit; Verma, Ashish S; Patel, Kalpeshkumar H et al. (2011) HIV-1 gp120 induces expression of IL-6 through a nuclear factor-kappa B-dependent mechanism: suppression by gp120 specific small interfering RNA. PLoS One 6:e21261
Kumar, Anil; Silverstein, Peter S (2011) New approaches to the inhibition of replication of viral pathogens. Expert Rev Anti Infect Ther 9:975-7