PB-1 7, 8 Dihydroxyflavone reduces mitochondrial dysregulation in the HIV-1 transgenic mouse model as a treatment for HIV associated Neurocognitive disorder (HAND)

Abstract

The introduction of combined antiretroviral therapy (cART) significantly increased the lifespan of HIV patients, turning a fatal disease to a chronic one. However, as a lower but persistent level of HIV infection remains, the susceptibility of HIV-associated neurocognitive disorder (HAND) is increased. Therefore, research is currently seeking improved treatment for this complication of HIV. 7, 8 Dihydroxyflavone (DHF) is a TrkB agonist that can cross the blood brain barrier and mimic the effect of Brain Derived Neurotrophic Factor (BDNF). Previous studies have described its potential as a treatment in a myriad of neurological diseases including Alzheimer's disease, peripheral sensory neuropathies, amyotrophic lateral sclerosis, Parkinson's disease, and Multiple Sclerosis. This study investigates mitochondrial dysregulation in the brain of HIV-1 Tg26 mice, a murine model of HIV, and the potential therapeutic effects of DHF treatment on this dysregulation in HAND. The mice were divided into 3 groups: wild type, untreated-Tg26, and DHF-treated Tg26 (Tg+DHF). Mice were sacrificed after 28 days and 7 µm thick paraffin sections of the brain of each mice were prepared. Tissues were immunohistochemically stained to detect the expression of mitochondria regulating proteins—SIRT3, PGC1-a, FIS-1, MFN-2, Citrate Synthase, SUR1, TRPM4—in the hippocampal and cortex regions. Our results show, that in these regions of Tg26 mice, SIRT3, PGC1-a, FIS-1, MFN-2, and Citrate Synthase were present in decreased levels, implicating the extensive role of mitochondrial dysfunction in HAND pathology. However, following DHF treatment, Tg26 mice expressed these cells at greater levels, suggesting a possible mechanism of DHF. Furthermore, both SUR1 and TRPM4 were upregulated in Tg26 mice. Previous studies have shown that SUR1 and TRPM4 often co-assemble to form an ion channel that plays a significant role in central nervous system injury and calcium homeostasis. Calcium is a regulator of mitochondrial dynamics, suggesting that the upregulation of SUR1 and TRPM4 may contribute to the mitochondrial changes that are characteristic to HAND. Interestingly, administration of DHF resulted in decreased expression of SUR1 and TRPM4. Therefore, the present study suggests that DHF treatment in the hippocampal and cortex regions of the TG26 model plays a role in reducing mitochondrial dysfunction by regulating calcium balance via the SUR1-TRPM4 ion channels, indicating its therapeutic potential as a treatment for HIV-associated neurocognitive disorder.