Mitochondrial biogenesis factor PGC-1α suppresses spinal morphine tolerance by reducing mitochondrial superoxide.

Opioid use disorders (OUDs) have reached an epidemic level in the United States. The opioid epidemic involves illicit opioid use, prescription opioids for analgesia, counterfeit opioids, new psychoactive substances, and diverted opioids. Opioids remain the last option for the treatment of intractable clinical pain, but chronic use of opioids are limited in part due to antinociceptive/analgesic tolerance. Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha (PGC-1α), a mitochondrial biogenesis factor can reduce toxic reactive oxygen species (ROS) that play a role in morphine tolerance (MT). Decreased PGC-1α expression has been shown to contribute to various metabolic disorders or neurodegeneration diseases through increasing ROS. We examined the relationship of PGC-1α and ROS in MT. To induce MT, adult Sprague-Dawley rats received intrathecal morphine for 7 days. Mechanical threshold was measured using the von Frey test and thermal latency was examined using the heat plate test. Expression of PGC-1α in the spinal cord dorsal horn (SCDH) was examined using RT-PCR and western blots. Mitochondrial superoxide was detected using MitoSox Red, a mitochondrial superoxide indicator. The antinociceptive effect of recombinant PGC-1α (rPGC-1α) or Mito-Tempol (a mitochondria-targeted superoxide scavenger) was determined using the von Frey test and hot plate test. Furthermore, we examined the effect of rPGC-1α on mitochondrial superoxide using cultured neurons. Our findings include that: (i) spinal MT decreased the expression of spinal PGC-1α in the SCDH neurons; (ii) rPGC-1α increased mechanical threshold and thermal latency in MT animals; (iii) Mito-Tempol reduced MT behavioral response; (iv) rPGC-1α reduced MT-induced mitochondria-targeted superoxide; and (v) cultured neuronal cells treated with TNFα increased mitochondria-targeted superoxide that can be inhibited by rPGC-1α. The present findings suggest that spinal PGC-1α reduce MT through decreasing mitochondria-targeted superoxide in the SCDH.

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-ß generation by reducing ß-secretase in an Alzheimer's disease model.

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aß pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of ß-APP cleaving enzyme (BACE1), the main enzyme involved in Aß generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aß deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aß pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.