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Alfred K Yu, Lanying Song, Karl Murray, Gino Cortopassi; Rapamycin rescues the innate immune/inflammatory response in the retina of the Ndufs4 mouse. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5541.
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© ARVO (1962-2015); The Authors (2016-present)
Mitochondrial complex I dysfunction has been shown to lead to vision loss via the loss of function of retinal ganglion cells (RGCs), however the mechanism of which that occurs in unclear. A recent study has shown that rapamycin treatment of Ndufs4 deficient mice alleviates mitochondrial disease and prolongs the life expectancy of these mice by reducing mTOR signaling. The goal of this study is to see the effects of rapamycin treatment in the retina of these mice by evaluating innate immune and inflammatory transcripts that we have already seen to increase in the Ndufs4 KO mouse. This will be valuable in developing therapeutics for mitochondrial visual diseases, such as Leber’s hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA).
Two Ndufs4 KO and two wild type controls received intraperitoneal injection (IP) of rapamycin (8mg/kg) daily for nine days starting from P22. Additionally, two Ndufs4 KO and two wild type controls received IP injection of vehicle. Experiments were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Visual Research. After nine days of treatment the nice were sacrificed and the retinas were surgically removed and placed in RNALater. Total RNA was extracted from the retinas and cDNA was synthesized for evaluation by qRT-PCR. The primers tested include: Fas, Tlr4, Ccl5, Ccl12, C1ra, Tlr3, Mmp12, Icam1, Cxcl9, Aif1, Tlr2, Cd68, C1qc, B2m, and Cxcl10. Analysis was done by calculating the delta delta Ct and statistical significance was determined by student’s t-test (2 tailed; equal variance).
Of the inflammatory transcripts tested, 16 out of 16 transcripts showed mean elevation compared to wild type controls, as was previously seen. Treatment with rapamycin inhibited the inflammatory response and the mean levels of all 16 transcripts rebounded and returned to values similar to wild type control, indicating that rapamycin suppresses inflammation that is downstream of mitochondrial dysfunction and may prevent neurodegeneration.
In the Ndufs4 retinal, mitochondrial complex I deficiency leads to vision loss, which is mediated by an innate immune and inflammatory response. Systemic treatment with rapamycin rescues this innate immune and inflammatory response and may prevent RGC death-mediated vision loss. This will provide therapeutic insight in mitochondrial diseases such as LHON and ADOA
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