The role of the arginine metabolome in pain: implications for sickle cell disease

Abstract

Sickle cell disease (SCD) is the most common hemoglobinopathy in the US, affecting approximately 100,000 individuals in the US and millions worldwide. Pain is the hallmark of SCD, and a subset of patients experience pain virtually all of the time. Of interest, the arginine metabolome is associated with several pain mechanisms highlighted in this review. Since SCD is an arginine deficiency syndrome, the contribution of the arginine metabolome to acute and chronic pain in SCD is a topic in need of further attention. Normal arginine metabolism is impaired in SCD through various mechanisms that contribute to endothelial dysfunction, vaso-occlusion, pulmonary complications, risk of leg ulcers, and early mortality. Arginine is a semiessential amino acid that serves as a substrate for protein synthesis and is the precursor to nitric oxide (NO), polyamines, proline, glutamate, creatine, and agmatine. Since arginine is involved in multiple metabolic processes, a deficiency of this amino acid has the potential to disrupt many cellular and organ functions. NO is a potent vasodilator that is depleted in SCD and may contribute to vaso-occlusive pain. As the obligate substrate for NO production, arginine also plays a mechanistic role in SCD-related pain, although its contribution to pain pathways likely extends beyond NO. Low global arginine bioavailability is associated with pain severity in both adults and children with SCD as well as other non-SCD pain syndromes. Preliminary clinical studies of arginine therapy in SCD demonstrate efficacy in treating acute vaso-occlusive pain, as well as leg ulcers and pulmonary hypertension. Restoration of arginine bioavailability through exogenous supplementation of arginine is, therefore, a promising therapeutic target. Phase II clinical trials of arginine therapy for sickle-related pain are underway and a Phase III randomized controlled trial is anticipated in the near future.

Precipitating factors and targeted therapies in combating the perils of sickle cell disease--- A special nutritional consideration

“…Arginine supplementation along with hydroxyurea increases level of HbF and nitrite [ 29 ]. Preliminarily outcome of phase 2 clinical trial showed that reduced arginine induces pain and vaso-occlusive crisis (VOC) which is alleviated through arginine supplementation in SCD patients [ 30 ].…”

Low nitric oxide level is implicated in sickle cell disease and its complications in Ghana

“… 33 , 36 NO-dependent blood flow is impaired in SCD patients. 27 , 40 , 41 Several studies have indicated the improvement of SCD and associated complications using arginine therapy, 42 – 44 due to the failure of NO-based therapeutic effect. 45 , 46 Thus, arginine supplementation may be required in the SCD patients with complications studied, especially those with VOC.…”

Sickle Cell Disease: Metabolomic Profiles of Vaso-Occlusive Crisis in Plasma and Erythrocytes

“…Glutamine (found here to decrease in the plasma) is related to both pain and NO metabolism and has been shown to mitigate pain in a phase III clinical trial in sickle cell disease [24]. Arginine metabolism also plays a key role in pain in sickle cell disease [10]. In effect, arginine supplementation has been shown to reduce pain via increased blood NO levels in a double-blind clinical trial [25].…”

“…It is worth noting that DMA and most of these amino acids are linked to arginine and nitric oxide (NO) metabolism. In effect, the steady state of the disease is known to be associated with a decrease in arginine concentration because of arginine consumption to synthesize ornithine, polyamines, proline, and glutamate (via arginase) rather than NO (via NO synthase) [9,10]. During hemolysis, arginase is liberated from red blood cells and competes with NO synthases for arginine consumption and, furthermore, free hemoglobin fixes NO.…”