RIC Therapy-Mediated Neuroprotection in Eye Trauma
Abstract
Traumatic Optic Neuropathy (TON) is a blunt or penetrating insult to the optic nerve, leading to partial or complete blindness, and is prevalent among both adults and children. War zones, motor vehicle accidents, and sports are events where TON injury happens (due to direct or indirect traumatic brain injury, TBI effect) and the person loses eyesight because of optic nerve/retinal degeneration. A significant population of military personnel is also affected by TBI during service and TBI causes TON later. Veterans also report TBI-like symptoms after returning from duty; however, these symptoms may not have been reported during their deployment, which suggests that there is a possibility where TBI-related TON may cause eyesight damage in Veterans. Following optic nerve injury, a sustained retinal inflammation and progressive demyelination of axonal architecture remains a critical barrier in preventing the progression of TON. To date, there are no therapies approved by the Food and Drug Administration to treat TON. Optic Nerve injury results in activation of resident microglia triggering retinal inflammation. Macrophages (Mphis) infiltrate site of injury, and polarize to either classically activated pro-inflammatory Mphi (M1) or alternatively activated anti-inflammatory Mphi (M2) phenotype and promote remyelination. Interestingly, the metabolic sensor, AMP-activated protein kinase alpha 1 (AMPKalpha1), plays a significant role in Mphi polarization and transcriptional regulation of interleukin-10 (IL-10), an anti-inflammatory cytokine that also polarizes Mphis to M2, attenuate demyelination and promotes remyelination in neurological disorders. However, a mechanistically driven therapeutic study of myeloid-specific AMPKalpha1/IL-10 in TON remains completely unexplored. Non-invasive Remote-limb Ischemic Conditioning (RIC) is the repetitive inflation-deflation of a blood pressure cuff on a limb to protect distant organs from ischemic injury and trauma. RIC therapy has been shown to improve the responsiveness of the retina and prevent retinal ganglion cell death after TON in mice and hamsters; however, the mechanistic insight and follow-up studies remain lacking. Our preliminary data shows that (1) RIC-activated myeloid AMPKalpha1 increased M2/M1 ratio in blood and elevated plasma level of IL-10; (2) RIC increased the IL-10 expression in retina, and suppressed the microglial activation; and (3) RIC prevented the loss of myelin basic protein, i.e., demyelination of optic nerve. Therefore, we hypothesize that RIC after optic nerve injury will prevent microglial activation and progression of TON in an IL-10 dependent manner via activation of myeloid AMPKalpha1. We propose the following specific aims: Specific Aim 1: Test the hypothesis that RIC after optic nerve injury attenuates retinal inflammation via activation of myeloid AMPKalpha1. We will use myeloid AMPKalpha1 conditional knockout and their control mice. We will demonstrate the functional role of myeloid-specific AMPKalpha1 in RIC therapy to attenuate retinal inflammation and the progression of TON. We will also examine optic nerve demyelination by electron microscopy and how RIC treatment reverses this process. Specific Aim 2: Test the hypothesis that RIC after optic nerve injury suppresses the progression of TON and preserves functional outcomes in an IL10-dependent manner. We will deplete IL-10 using IL-10 antibody and demonstrate that RIC after optic nerve injury prevents the demyelination of axonal architecture and progression of TON via an IL10-dependent pathway. Expected Outcomes: RIC therapy after optic nerve injury suppresses microglial activation, retinal inflammation, and demyelination of optic nerve via activation of the myeloid AMPKalpha1/IL-10 immune pathway. There is an unmet need for effective and safe treatments for TON. Preclinical data focusing on the novel risk factors and possible molecular mechanisms underlying the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210673
Entities
People
- Saif Ahmad
Organizations
- United States Army