Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway

Abstract

Retinal ischemia-reperfusion (RIR) injury causes neuronal degeneration and initiates various optic nerve diseases. This study aimed to investigate the synergistic neuroprotective effect of rasagiline and idebenone against RIR injury. A combination of rasagiline and idebenone was administered intraperitoneally immediately after establishment of the RIR model. Treatment with the combination of the two drugs resulted in a significant restoration of retinal thickness and retinal ganglion cells. Apoptosis of cells in ganglion cell layers was also ameliorated, suggesting that the effect of the two drugs was synergistic and the expression of brain-derived neurotrophic factor increased. Furthermore, idebenone and rasagiline induced the expression of Lin28A and Lin28B, respectively, which resulted in a reduced expression of microRNAs in the let-7 family and an increased protein output of Dicer. The data obtained from gene overexpression and knockdown experiments indicated that let-7 and Dicer were necessary for the synergistic neuroprotective effect of the two drugs. Our findings suggested that combination therapy with rasagiline and idebenone produced a synergistic effect that ameliorated RIR injury and restored visual function. In addition, the combined treatment provided neuroprotection via enhancement of the selective regulation of let-7 by Lin28A/B. These findings implied that a treatment with the combination of rasagiline and idebenone is a feasible treatment option for optic nerve diseases.

Multi-Level Regulatory Interactions between NF-κB and the Pluripotency Factor Lin28

“…The tissue and cellular expression profiles for Lin28a and Lin28b in mammals remain somewhat enigmatic, with low or undetectable levels reported in adults for most regions, with the exception of the testes, in atlas sources for mouse and human (e.g., ). This stands in possible discrepancy to accumulating reports of Lin28a and Lin28b presence and function in adult organisms or differentiated cells and tissues [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], despite clear downregulation in levels from early development. Ineffective detection is not unfamiliar amongst low abundance proteins and transcripts which may not be readily quantified or documented in databases and could be contributed to by a failure to capture signal-dependent upregulation.…”

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…Several protective drugs modulate other independent routes that may alternatively be activated during reperfusion and that are not assigned to the RISK, SAFE or the cGMP/PKC pathways. They can have different types of effects such as such as inhibition of ROS-producing complexes [18,67,134,135,136,137,138,139,140,141,142,143], or may act as anti-apoptotic [144], anti-inflammatory [24,53,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164] and antioxidants agents [165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194], as glucose metabolism enhancers [99,…”

“…The mechanisms vary greatly and may be roughly summarized as activation of protective pathways (mostly suppression of mitophagy) and neutralization of free radicals and other reactive oxidizing species. Some prominent agents are aldehyde dehydrogenase 2 [165,166,167,169,170], candesartan [153], minocycline [153,172], melatonin [97,173,174,177] [225], exogenous NADPH [378], glutathione [96,98,179,180,379], N -acetylcysteine (NAC) [98,180,181,182,183,184], calmangafodipir [185], mangafodipir [185,186,187], superoxide dismutase [188,189,190,191,192], diltiazem [191], idebenone [193], rasagiline, and idebenone [194].…”

Thermo-Responsive PLGA-PEG-PLGA Hydrogels as Novel Injectable Platforms for Neuroprotective Combined Therapies in the Treatment of Retinal Degenerative Diseases

“…Recently, the partially soluble analogue of Q10 coenzyme known as idebenone has gained much interest as a neuroprotective therapy for Alzheimer, Parkinson and retinal degeneration. Idebenone has been described as possessing a strong antioxidant activity that is currently being intensively studied and could entail an interesting option in combined therapy for neuroprotection in retinal degenerative diseases [ 22 ].…”