Co‐administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats

Abstract

Psychostimulant methamphetamine (METH) is toxic to dopaminergic and serotonergic striatal nerve terminals in adult, but not in adolescent, brain. Betulinic acid (BA) and its derivatives are promising anti-HIV agents with some toxic properties. Many METH users, particularly young men, are HIV-positive; therefore, they might be treated with BA or its derivative for HIV infection. It is not known whether BA, or any of its derivatives, is neurotoxic in combination with METH in adolescent brain. The present study investigated the effects of BA and binge METH in the striatum in late adolescent rats. BA or METH alone did not decrease the levels of dopaminergic or serotonergic markers in the striatum whereas BA and METH together decreased these markers in a BA dose-dependent manner. BA and METH combination also caused decreases in the levels of mitochondrial complex I in the same manner; BA alone only slightly decreased the levels of the enzyme in striatal synaptosomes. BA or METH alone increased cytochrome c. METH alone decreased parkin, increased complex II and striatal BA levels. These results suggest that METH in combination with BA can be neurotoxic to dopaminergic and serotonergic striatal nerve terminals in late adolescent brain via mitochondrial dysfunction and parkin deficit.

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

“…On the contrary, the exposure of late adolescent male rats to nanomolar concentrations of BetA and high‐dose binge methamphetamine induces toxicity to striated dopaminergic and serotonergic nerve terminals in the brain. This neurotoxicity is preceded by a BetA dose‐dependent decrease in the mitochondrial complex I as well as by dose‐independent increases in complex II and cytochrome C in striatal terminals . This finding is of special interest, as BetA exhibits anti‐HIV activity, and many derivatives of BetA have improved upon its antiviral activity.…”

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

“…However, the mechanisms underlying the specific targets of BA during ER stress remain elusive. Furthermore, BA has been shown to cross the BBB; at 3 h after BA injection, its concentrations in brain and in plasma reached peak values of 38.6 ± 3.2 ng/g and 207.9 ± 34.5 ng/mL, respectively [16].…”

Self‐administration of methamphetamine alters gut biomarkers of toxicity

“…High doses (4 × 7.5 or 10 mg/kg, every 2 h) of non‐contingently‐administered binge METH lead to parkin deficits of 28–34% in the striatum at 1 and 24 h after the last injection of the drug in rats (Moszczynska & Yamamoto, ; Killinger et al ., ). In the rat myenteric plexus, we observed a 58% decrease in total parkin immunoreactivity, a 61% decrease in parkin‐neurofilament co‐localization, and a 17% decrease in intensity of parkin signal within the co‐localization area at 1 day after the cessation of METH self‐administration.…”

“…These results suggest that parkin levels decreased mainly within the neurofilament‐positive neurons, such as Dogiel type II neurons, which are primary afferent neurons in the myenteric plexus (Brehmer, ). Given low dose of self‐administered METH, compared to the doses in the binge protocols (Moszczynska & Yamamoto, ; Killinger et al ., ), it may be that gut parkin is more sensitive to the METH‐induced oxidative damage in the ENS than it is in the CNS. In the CNS, the deficit in parkin is caused by oxidative damage to the protein induced by DA‐dependent oxidative stress (LaVoie et al ., , ; Moszczynska & Yamamoto, ).…”