Behavioral and neurochemical effects of proline

Abstract

Proline is an amino acid with an essential role for primary metabolism and physiologic functions. Hyperprolinemia results from the deficiency of specific enzymes for proline catabolism, leading to tissue accumulation of this amino acid. Hyperprolinemic patients can present neurological symptoms and brain abnormalities, whose aetiopathogenesis is poorly understood. This review addresses some of the findings obtained, mainly from animal studies, indicating that high proline levels may be associated to neuropathophysiology of some disorders. In this context, it has been suggested that energy metabolism deficit, Na(+),K(+)-ATPase, kinase creatine, oxidative stress, excitotoxicity, lipid content, as well as purinergic and cholinergic systems are involved in the effect of proline on brain damage and spatial memory deficit. The discussion focuses on the relatively low antioxidant defenses of the brain and the vulnerability of neural tissue to reactive species. This offers new perspectives for potential therapeutic strategies for this condition, which may include the early use of appropriate antioxidants as a novel adjuvant therapy, besides the usual treatment based on special diets poor in proline.

Experimental hyperprolinemia induces mild oxidative stress, metabolic changes, and tissue adaptation in rat liver

“…To our knowledge, there are no studies showing the effects of hyperprolinemia on oxidative and metabolic status in liver. Our data reinforce the hypothesis that proline and its interconversions function as a unique mechanism for redox balance [Araujo et al, 2001;Krishnan et al, 2008;Phang et al, 2010;Wyse and Netto, 2011], which may be related to increased levels of this amino acid in hepatic diseases. Also, we cannot rule out that liver, as a central organ for metabolism, fulfill the role to counterbalance the oxidative and metabolic effects of systemic hyperprolinemia.…”

“…Studies addressing the proline metabolism in plants, fungi, and mammals suggest that this amino acid may have opposing effects on the intracellular redox environment [Krishnan et al, 2008;Phang et al, 2010;Wyse and Netto, 2011]. Because the catabolism of this amino acid involves the transfer of electrons from substrate proline to flavine adenine dinucleotide (FAD), proline may be a direct substrate for the generation of ATP [Hagedorn and Phang, 1983].…”

Structural Determinants of Oligomerization of Δ1-Pyrroline-5-Carboxylate Dehydrogenase: Identification of a Hexamerization Hot Spot

“…4-8 Certain missense and frameshift mutations in the gene encoding P5CDH abrogate enzyme function, resulting in elevated levels of P5C and proline in plasma, urine, and cerebrospinal fluid. 9 Type II hyperprolinemia is causally linked to neurologic manifestations, such as increased incidence of seizures and intellectual and developmental disabilities, 10 although exactly how the enzyme deficiency contributes to these conditions is unclear. Possible mechanisms involve the role of proline as a neurotransmitter, 11-14 oxidative stress, 9 and mitochondrial dysfunction.…”

“…9 Type II hyperprolinemia is causally linked to neurologic manifestations, such as increased incidence of seizures and intellectual and developmental disabilities, 10 although exactly how the enzyme deficiency contributes to these conditions is unclear. Possible mechanisms involve the role of proline as a neurotransmitter, 11-14 oxidative stress, 9 and mitochondrial dysfunction. 15 …”

Evidence that Hyperprolinemia Alters Glutamatergic Homeostasis in Rat Brain: Neuroprotector Effect of Guanosine

“…Enzymatic deficiencies of proline oxidase and D 1 -pyrroline-5-carboxylic acid dehydrogenase give rise to hyperprolinemia type I (HPI) and hyperprolinemia type II (HPII), respectively [1,2]. Although both enzymes deficiencies lead to tissue accumulation of proline, HPII causes higher plasma levels, which has been related to neurological manifestations such as seizures and mental retardation [1][2][3].…”