Methamphetamine use disorder (MUD) is associated with chronic inflammation in the brain. It also has a very high relapse rate – a recent University of Nebraska-Lincoln study reports that meth use and overdose deaths are rising in rural parts of the state.
Are those two things – inflammation in the brain and methamphetamine use disorder relapses – related?
A University of Nebraska Medical Center–UNL research team, led by Sowmya Yelamanchili, PhD, associate professor of anesthesiology in the UNMC Department of Anesthesiology, recently published findings in a leading medical journal that establish that connection and much more.
Dr. Yelamanchili and her team report that the microRNA mir-29a “plays a critical role in (chronic methamphetamine exposure)-induced inflammation and damage to the synapses.” Mir-29a is significantly increased during methamphetamine exposure.
Further, the study found that mir-29a levels show significant increase both with drug-seeking and “reinstatement,” a model of relapse, in animal models. An anti-inflammatory agent, already an FDA-approved drug for other conditions, can reduce levels of mir-29a and “thereby rescue relapse in animals,” Dr. Yelamanchili said.
Through study of plasma from human methamphetamine use disorder subjects, the team has validated mir-29a as a biomarker to detect chronic inflammation and synaptic damage.
These findings show, “The presence of this microRNA can cause relapse,” Dr. Yelamanchili said.
“We are excited to have found this critical lead.”
Publication in the field’s leading journal, the Journal of Extracellular Vesicles, means the scientific community believes the findings are a big deal. “It means these works have a high translational relevance,” Dr. Yelamanchili said.
“We have covered the entire gamut of addiction,” said Gurudutt Pendyala, PhD, Robert Lieberman Professor of Anesthesiology.
Dr. Pendyala is a crucial collaborator, as are Howard Fox, MD, PhD, professor of neurological sciences, and Rick Bevins, PhD, director of UNL’s Rural Drug Addiction Research Center.
EV-miR29a causes synaptodendritic injury in primary cortical neurons
Wild-type (WT) and TLR7 knock out (TLR7-/-) mouse cortical neurons were incubated with 1 μg of synthetic miRNAs; miR-29a, miR-29a containing a mutation in TLR7 binding site (miR29aUG) and a knownTLR7 agonist, Imiquimod, and DOTAP. Neurons were incubated for 24 h and then stained with MAP2 for neurons; PSD95 to mark the a post-synapse, VGLUT1 for pre-synapse and Drebrin for staining the dendritic spines. The number of PSD95/VGLUT1 co-localised puncta were counted and quantified in both (a) WT and (b) TLR7-/- neuronal cultures. (c) Quantification of the data from the WT cultures indicates a significant decrease in synapses as observed by a significant decrease in VGLUT1/PSD-95 puncta from miR-29a:DOTAP as well as in Imiquimod treated cultures when compared to miR29a-UG or vehicle (DOTAP) control.
The comprehensive study has been a five-year journey for Dr. Yelamanchili and team. She first got the idea studying how extracellular vesicles — organelles regulating several body functions, including carrying cargo molecules (in this case microRNA from cell to cell) — contribute to inflammation in other diseases. Nebraska is first to connect this to MUD.
The team further validated its findings using in vitro cultures, where introducing mir-29a caused damage to synapses, and finally human subject plasma, lending a high degree of translational relevance.
In preclinical animal models, treatment with the anti-inflammatory ibudilast decreased mir-29a, lessened inflammation and “rescued” damage to the synapses and dendrites. The team, funded through a National Institutes of Health R01 grant, is actively pursuing further therapeutics study and aims to move into clinical subjects, hopefully within a couple years.
Working for fellow Nebraskans
Methamphetamine use disorder (MUD) “is a complex brain disease that affects an individual’s well-being and can also affect their entire family,” according to the National Center on Substance Abuse and Child Welfare. This human concern drives Sowmya Yelamanchili, PhD, Gurudutt Pendyala, PhD, Howard Fox, MD, PhD, and their UNMC teams, in collaboration with Rick Bevins, PhD, and UNL’s Rural Drug Addiction Research Center.
These investigators strive to make their lab research translational, so that it reaches their fellow Nebraskans, some of whom have been devastated by the effects of methamphetamine use disorder.
“It is very debilitating and stressful, not just for the person taking it, but for the entire society, family members,” Dr. Yelamanchili said.
A 2021 Rural Drug Addiction Research Center report noted that psychostimulant-involved overdose deaths had increased by 58.8% in Nebraska since 2018.
“This is a problem that is very close to us here at home in Nebraska,” Dr. Pendyala said. “We will see how translational this work will become, how it can help the people suffering from this disorder.”
Dr. Pendyala said he hopes this study brings “a ray of hope.”