Combined drug triads for synergic neuroprotection in retinal degeneration

Maneu, Victoria; Lax, Pedro; Diego, Antonio M. G. de; Cuenca, Nicolás; Garcı́a, Antonio G.

doi:10.1016/j.biopha.2022.112911

Cited by 9 publications

(6 citation statements)

References 381 publications

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“…Combined efficacy of citicoline with CoQ10 has been demonstrated in many retinal pathologies including glaucoma ( 8 ). Accordingly, combined drug treatments acting by multitarget approach have been shown to be more effective compared with single-drug treatments ( 48 ). In combination, drugs could be used at doses lower than standard, thus displaying safer and more efficient activity.…”

Section: Discussionmentioning

confidence: 99%

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Melecchi,

Amato,

Dal Monte

et al. 2023

Front. Med.

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IntroductionMuch interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase.MethodsOcular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis.ResultsThe present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination.ConclusionNiacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.

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Section: Discussionmentioning

confidence: 99%

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Melecchi,

Amato,

Dal Monte

et al. 2023

Front. Med.

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“…In this regard, the neuroprotective strategies identify and target the potential molecular pathways intended to delay or prevent the death of RGCs by mitigating the proapoptotic process. 8,9 Bioactive sphingolipids-ceramide, sphingosine, and sphingosine-1-phosphate (S1P)-are signaling molecules that regulate diverse cellular functions, including cell survival, growth, migration, and differentiation in the retina and the brain. [10][11][12] Particularly, S1P activates five G-protein-coupled receptors termed S1PR1-5 and are implicated in the pathogenesis of different neurodegenerative diseases in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

“…Identifying the underlying molecular pathways of RGC survival in glaucoma could lead to the development of new protective therapeutics. In this regard, the neuroprotective strategies identify and target the potential molecular pathways intended to delay or prevent the death of RGCs by mitigating the proapoptotic process 8,9 …”

Section: Introductionmentioning

confidence: 99%

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

et al. 2022

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Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1‐phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1/2 activation and attenuated the apoptotic signaling via suppression of c‐Jun/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt/Erk1/2 activation, c‐Jun/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c‐Jun/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.

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“…8 Investigations indicated that erythropoietin 18 and blockage of purinergic P2X7 receptor, an inflammation mediator, are beneficial on neuroprotection in rat glaucoma models. 19…”

Section: Glaucomamentioning

confidence: 99%

“…The generally accepted therapeutic strategies for glaucoma are topical ocular hypotensive drops, laser therapy, and surgical intervention to reduce the risk of further progression 8 . Investigations indicated that erythropoietin 18 and blockage of purinergic P2X7 receptor, an inflammation mediator, are beneficial on neuroprotection in rat glaucoma models 19 …”

Section: Optic Neuropathiesmentioning

confidence: 99%

Optic nerve diseases and regeneration: How far are we from the promised land?

Cen

Park

2023

Clinical Exper Ophthalmology

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The retinal ganglion cells (RGCs) are the sole output neurons that connect information from the retina to the brain. Optic neuropathies such as glaucoma, trauma, inflammation, ischemia and hereditary optic neuropathy can cause RGC loss and axon damage, and lead to partial or total loss of vision, which is an irreversible process in mammals. The accurate diagnoses of optic neuropathies are crucial for timely treatments to prevent irrevocable RGCs loss. After severe ON damage in optic neuropathies, promoting RGC axon regeneration is vital for restoring vision. Clearance of neuronal debris, decreased intrinsic growth capacity, and the presence of inhibitory factors have been shown to contribute to the failure of post‐traumatic CNS regeneration. Here, we review the current understanding of manifestations and treatments of various common optic neuropathies. We also summarise the current known mechanisms of RGC survival and axon regeneration in mammals, including specific intrinsic signalling pathways, key transcription factors, reprogramming genes, inflammation‐related regeneration factors, stem cell therapy, and combination therapies. Significant differences in RGC subtypes in survival and regenerative capacity after injury have also been found. Finally, we highlight the developmental states and non‐mammalian species that are capable of regenerating RGC axons after injury, and cellular state reprogramming for neural repair.

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Combined drug triads for synergic neuroprotection in retinal degeneration

Cited by 9 publications

References 381 publications

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

Optic nerve diseases and regeneration: How far are we from the promised land?

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