Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cδ has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA.
Background
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease, characterised by oligodendrocyte death and demyelination. Oligodendrocyte progenitor cells can differentiate into new replacement oligodendrocytes; however, remyelination is insufficient to protect neurons from degeneration in people with MS. We previously reported that 4 weeks of daily low-intensity repetitive transcranial magnetic stimulation (rTMS) in an intermittent theta-burst stimulation (iTBS) pattern increased the number of new myelinating oligodendrocytes in healthy adult mice. This study translates this rTMS protocol and aims to determine its safety and tolerability for people living with MS. We will also perform magnetic resonance imaging (MRI) and symptom assessments as preliminary indicators of myelin addition following rTMS.
Methods
Participants (N = 30, aged 18–65 years) will have a diagnosis of relapsing-remitting or secondary progressive MS. ≤2 weeks before the intervention, eligible, consenting participants will complete a physical exam, baseline brain MRI scan and participant-reported MS symptom assessments [questionnaires: Fatigue Severity Scale, Quality of Life (AQoL-8D), Hospital Anxiety and Depression Scale; and smartphone-based measures of cognition (electronic symbol digit modalities test), manual dexterity (pinching test, draw a shape test) and gait (U-Turn test)]. Participants will be pseudo-randomly allocated to rTMS (n=20) or sham (placebo; n=10), stratified by sex. rTMS or sham will be delivered 5 days per week for 4 consecutive weeks (20 sessions, 6 min per day). rTMS will be applied using a 90-mm circular coil at low-intensity (25% maximum stimulator output) in an iTBS pattern. For sham, the coil will be oriented 90° to the scalp, preventing the magnetic field from stimulating the brain. Adverse events will be recorded daily. We will evaluate participant blinding after the first, 10th and final session. After the final session, participants will repeat symptom assessments and brain MRI, for comparison with baseline. Participant-reported assessments will be repeated at 4-month post-allocation follow-up.
Discussion
This study will determine whether this rTMS protocol is safe and tolerable for people with MS. MRI and participant-reported symptom assessments will serve as preliminary indications of rTMS efficacy for myelin addition to inform further studies.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12619001196134. Registered on 27 August 2019
We have previously demonstrated that repeated treatment with methamphetamine (MA) results in a recognition memory impairment via upregulation of protein kinase C (PKC) δ and downregulation of the glutathione peroxidase-1 (GPx-1)-dependent antioxidant system. We also demonstrated that far-infrared ray (FIR) attenuates acute restraint stress via induction of the GPx-1 gene. Herein, we investigated whether exposure to FIR modulates MA-induced recognition memory impairment in male mice, and whether cognitive potentials mediated by FIR require modulation of the PKCδ gene, extracellular signal-regulated kinase (ERK) 1/2, and glutathione-dependent system. Repeated treatment with MA significantly increased PKCδ expression and its phosphorylation out of PKC isoenzymes (i.e., PKCα, PKCβI, PKCβII, PKCζ, and PKCδ expression) in the prefrontal cortex of mice. Exposure to FIR significantly attenuated MA-induced increase in phospho-PKCδ and decrease in phospho-ERK 1/2. In addition, FIR further facilitated the nuclear factor E2-related factor 2 (Nrf2)-dependent glutathione synthetic system. Moreover, L-buthionine-(S, R)-sulfoximine, an inhibitor of glutathione synthesis, counteracted the FIR-mediated phospho-ERK 1/2 induction and memory-enhancing activity against MA insult. More important, positive effects of FIR are comparable to those of genetic depletion of PKCδ or the antipsychotic clozapine. Our results indicate that FIR protects against MA-induced memory impairment via activations of the Nrf2-dependent glutathione synthetic system, and ERK 1/2 signaling by inhibition of the PKCδ gene.
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