Creatine and Energy Buffering in Retinal and Optic Nerve Tissues

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IntroductionRetinal ganglion cells (RGCs) are the neurons that send visual signals from the eye to the brain. They rely on a high-energy metabolism because they must maintain electrical signals over long distances. In glaucoma and related optic neuropathies, elevated intraocular pressure (IOP) or poor blood flow can stress RGCs by limiting oxygen and nutrients. Emerging evidence suggests that RGCs under pressure-induced stress suffer early energy failure – their ATP levels drop before any visible cell loss (). Thus, therapies that boost cellular energy might protect RGCs from degeneration. One candidate is creatine, a compound cells use to buffer energy. This article reviews how creatine and its high-energy form phosphocreatine (PCr) support RGCs under stress, and what this could mean for glaucoma and aging.The Creatine–Phosphocreatine Energy BufferCreatine is a natural molecule made in the liver, kidney and pancreas (from arginine, glycine, methionine) and stored mostly in muscle (≈95%) and also in brain and other tissues () (). Inside cells, creatine is converted back and forth to phosphocreatine (PCr) by the enzyme creatine kinase (CK). This PCr–CREATINE system serves as an energy buffer: when ATP is used up quickly (for example during muscle contraction or neuron signaling), PCr donates its phosphate to adenosine diphosphate (ADP) to reform ATP. Simply put, PCr can regenerate ATP far more quickly than mitochondria alone (). In practical terms, within a few seconds of intense activity, a resting cell’s ATP is depleted, but the CK system steps in by converting PCr back to ATP to keep energy levels stable (). After the burst of activity, excess ATP can again recharge creatine back into PCr for the next cycle. This reversible cycle makes creatine/PCr a “ready reserve” of energy, especially important in cells with high and rapid energy needs () (). Importantly, this system exists not only in muscle but in nerve cells. Neurons (including RGCs) express CK isoforms that enable them to use creatine. In fact, retinal neurons express predominantly mitochondrial CK, while retinal glial cells use cytosolic CKs (). By storing a pool of PCr in cells, tissues like the retina can get an instant ATP supply when needed.Creatine in the Retina and Optic NerveRole of Creatine in RGC Metabolism In the retina, RGCs have very high energy demands. Even brief impulses require substantial ATP for ion pumps and signaling. When IOP rises or blood flow drops, RGCs can become ischemic, meaning oxygen and nutrients can’t meet demand. In such situations, the PCr reserve is crucial. Research notes that when optic nerve blood flow is poor (as may happen in glaucoma), tissues rely on PCr to keep ATP levels from crashing (). In other words, phosphocreatine acts as a local energy “battery” that RGCs can draw on during stress (). Experimental work in other nerves supports this: adding creatine before an induced ischemia protected brain axons and prevented ATP depletion (). These findings suggest RGCs could similarly benefit from extra creatine under IOP-induced stress. The idea is that if RGCs are better able to maintain ATP via the CK–PCr system, they might resist damage and death.Laboratory Studies of Creatine and Retinal NeuronsSeveral studies have tested creatine’s effect on retinal neurons. In rat retinal cell cultures, adding creatine to the medium protected neurons (including RGCs) from death due to metabolic toxins or glutamate excitotoxicity (). In those in vitro experiments, creatine dram