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S. Chollangi, J. Wang, J. D. Ash; Survival Pathways Downstream Cyclic Bright Light-Induced Endogenous Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2990. doi: https://doi.org/.
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Preconditioning with moderate oxidative stress (e.g. light-induced stress, mechanical stress or hypoxic stress) can induce changes in retinal tissue which protect photoreceptors from a subsequent lethal dose of oxidative stress. Three important pathways that are known to prevent cell death include PI3K/Akt, MAPK/ERK1/2 and Jak/STAT3. Our purpose is to determine which of these pathways play a role in protecting the photoreceptors following cyclic bright light preconditioning.
Balb/cj mice (WT or Akt2-/-), aged 5-6 weeks, were preconditioned with 12 hour cyclic bright light (600lux; 6AM to 6PM) for 6 days before being subjected to severe light stress (4 hours at 4000lux). Photoreceptor function was measured using electroretinography (ERGs) and histological analysis. Activation of signal transduction pathways was measured by western blots and immunohistochemistry.
Under normal conditions, all of the survival pathways (Akt, ERK1/2 or STAT3) exhibited either very low levels or no activation based on western blot analysis. However, upon preconditioning with cyclic bright light, STAT3 exhibited robust time dependent activation while Akt and ERK1/2 showed no increase in activation. Akt2-/- mice exhibited normal cyclic bright light-induced retinal protection.
Our results demonstrate that upon preconditioning with cyclic bright light, STAT3 pathway is activated rather than Akt or ERK1/2. Without preconditioning, genetic deletion of Akt2 (Akt2-/- mice) resulted in increased sensitivity to light damage. However, after subjecting to cyclic bright light preconditioning these mice exhibited normal endogenous protection suggesting that Akt2 does not participate in this protection model. In conclusion, our study indicates that STAT3 activation is important for the cyclic bright light-induced endogenous neuroprotection of the retinal photoreceptors.
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