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

Abstract

This study investigated the effects of acute and chronic hyperprolinemia on glutamate uptake, as well as some mechanisms underlying the proline effects on glutamatergic system in rat cerebral cortex. The protective role of guanosine on effects mediated by proline was also evaluated. Results showed that acute and chronic hyperprolinemia reduced glutamate uptake, Na(+), K(+)-ATPase activity, ATP levels and increased lipoperoxidation. GLAST and GLT-1 immunocontent were increased in acute, but not in chronic hyperprolinemic rats. Our data suggest that the effects of proline on glutamate uptake may be mediated by lipid peroxidation and disruption of Na(+), K(+)-ATPase activity, but not by decreasing in glutamate transporters. This probably induces excitotoxicity and subsequent energy deficit. Guanosine was effective to prevent most of the effects promoted by proline, reinforcing its modulator role in counteracting the glutamate toxicity. However, further studies are needed to assess the modulatory effects of guanosine on experimental hyperprolinemia.

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

“…Glutamine is a precursor of glutamate and gamma-aminobutyric acid [50], and altered levels of circulating glutamine may affect the gamma-aminobutyric acid levels in the brain [51]. Proline is synthesized from glutamic acid, and chronic hyperprolinemia can lead to reduced glutamate uptake, increased adenosine triphosphate catabolism, and increased pro-inflammatory cytokine levels [52][53][54]. Moreover, monoamine neurotransmitters may be involved in MDD, as tryptophan is the precursor for serotonin and tyrosine is the precursor for catecholamines.…”

Vitamin D insufficiency and schizophrenia risk: Evaluation of hyperprolinemia as a mediator of association

“…Proline can also modulate glutamatergic neurotransmission, as supported by the specificity of proline active uptake to a subset of glutamatergic terminals, its ability to inhibit glutamate release at high concentrations, and the finding of reduced glutamate uptake in the hyperprolinemic rat brain (Phang et al, 2001; Cohen and Nadler, 1997; Ferreira et al, 2012). While studies of elevated proline in humans (22q11DS patients (Karayiorgou et al, 2004), hyperprolinemia types I and II (Phang et al, 2001)) and a chronic proline administration model (Shanti et al, 2004), have documented the pathogenic properties of hyperprolinemia, the consequences of elevated proline for CNS neurotransmission have been best demonstrated by work on the hyperprolinemic Prodh null mouse (Gogos et al, 1999; Paterlini et al, 2005), which in the presence of POX deficiency and elevated proline (peripheral and CNS), exhibits a deficit in sensorimotor gating, increased sensitivity to amphetamine, and impairments in declarative memory, coupled with locally decreased CNS glutamate and GABA, increased neurotransmitter release at glutamatergic synapses, and possible activation of dopaminergic signaling.…”

PRODH rs450046 and proline x COMT Val158Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome

“…Proline has been shown to modulate glutamate neurotransmission and to have effects on the NMDA receptor (Ferreira et al 2012). PRODH hemizygosity probably leads to lower POX activity, and indeed increased plasma proline levels have been demonstrated in patients with 22q11DS (Goodman et al 2000).…”

“…PRODH hemizygosity probably leads to lower POX activity, and indeed increased plasma proline levels have been demonstrated in patients with 22q11DS (Goodman et al 2000). There is growing evidence that high proline levels may predispose to brain damage (Ferreira et al 2012). Severe hyperprolinemia (>550 μmol/L) is seen in children with type I hyperprolinemia (HPI), an autosomal recessive disorder consisting of inherited deficiency of POX, and has been associated with seizures, intellectual disability and psychiatric symptoms; all of these are also associated with 22q11DS (Jacquet et al 2003;Raux et al 2007).…”