Preventive Effects of Duloxetine Against Methamphetamine Induced Neurodegeneration and Motor Activity Disorder in Rat: Possible Role of CREB/BDNF Signaling Pathway

Abstract

Background: The neuroprotective effects of duloxetine and neurodegenerative effects of
methamphetamine have been shown in previous studies, but their exact mechanism remain unclear.
In the current study it involved molecular mechanisms of neuroprotective effects of duloxetine
against methamphetamine induced neurodegeneration were clarified.

Methods: About 40 adult
male rats randomly were divided to 5 groups. Group 1 and 2, as control and methamphetamine
treated, received normal saline and methamphetamine (10 mg/kg) respectively. Groups 3, 4 and
5 concurrently treated with methamphetamine and duloxetine at doses of 10, 20 and 30 mg/kg
respectively. All treatments were undertaken for 21 days. On day 22 Open Field Test (OFT) were used
to examine the level of motor activity disturbance and anxiety in animals. After that hippocampus
was isolated from each rat and oxidative, antioxidant, inflammatory factors and also level or
expression of total and phosphorylated forms of CREB and P‑CREB and BDNF proteins were
measured.

Results: Duloxetine in all mentioned doses could inhibit the effects of methamphetamine
induced motor activity disturbance in MWM. Chronic abuse of methamphetamine could increase
malondialdehyde (MDA), tumor necrosis factor‑Alpha (TNF‑α) and interleukine‑1beta (IL‑1β) while
caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione
reductase (GR) activities and decreased CREB (both forms) and BDNF proteins, while duloxetine
could prevent these malicious effects of methamphetamine.

Conclusions: We conclude that P‑CREB/
BDNF signaling pathways might have critical role in duloxetine neuroprotective effects against
methamphetamine induced neurodegeneration.

Keyword: Duloxetine, methamphetamine, motor activity, neurodegeneration, P‑CREB/BDNF
pathway