Influence of Proline on Rat Brain Activities of Alanine Aminotransferase, Aspartate Aminotransferase and Acid Phosphatase

Abstract

Hyperprolinemia type II (HPII) is an autosomal recessive disorder caused by the severe deficiency of enzyme delta1-pyrroline-5-carboxylic acid dehydrogenase leading to tissue accumulation of proline. Chronic administration of Pro led to significant reduction of cytosolic ALT activity of olfactory lobes (50.57%), cerebrum (40%) and medulla oblongata (13.71%) only. Whereas mitochondrial ALT activity was reduced significantly in, all brain regions such as olfactory lobes (73.23%), cerebrum (70.26%), cerebellum (65.39%) and medulla oblongata (65.18%). The effect of chronic Pro administration on cytosolic AST activity was also determined. The cytosolic AST activity from olfactory lobes, cerebrum and medulla oblongata reduced by 75.71, 67.53 and 76.13%, respectively while cytosolic AST activity from cerebellum increased by 28.05%. The mitochondrial AST activity lowered in olfactory lobes (by 72.45%), cerebrum (by 78%), cerebellum (by 49.56%) and medulla oblongata (by 69.30%). In vitro studies also showed increase in brain tissue proline and decrease in glutamate levels. In vitro studies indicated that proline has direct inhibitory effect on these enzymes and glutamate levels in brain tissue showed positive correlation with AST and ALT activities. Acid phosphatase (ACP) activity reduced significantly in olfactory lobes (40.33%) and cerebrum (20.82%) whereas it elevated in cerebellum (97.32%) and medulla oblongata (76.33%). The histological studies showed degenerative changes in brain. Following proline treatment, the animals became sluggish and showed low responses to tail pricks and lifting by tails and showed impaired balancing. These observations indicate influence of proline on AST, ALT and ACP activities of different brain regions leading to lesser synthesis of glutamate thereby causing neurological dysfunctions.

Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome

“…Interestingly, the largest study of VCFS patients reported a significantly later onset of schizophrenia in the 22q11DS patients (mean age 26 years) compared to a control group of unrelated schizophrenic patients (mean age 19 years)(Murphy et al 1999). That study along, with our finding, may thus point to etiological differences between patients with and without hyperprolinemia: Clinically elevated peripheral proline is reflected by elevation in the CNS (Baxter et al 1985; Dingman and Sporn 1959; Efron 1965; Gogos et al 1999; Jacquet et al 2003; Shanti et al 2004), and we hypothesize that the elevated plasma proline in schizophrenia also reflects elevated CNS levels in these subjects. Speculatively, it may be that chronically elevated CNS proline increases risk for development of schizophrenia, but that long-term exposure is necessary for this effect to manifest.…”

“…P5C dehydrogenase deficits and the resultant hyperprolinemia can lead to low IQ, seizures, and in some subjects, mild mental retardation (Flynn et al 1989). Following chronic proline administration, rats with plasma proline levels consistent with human HPII developed behavioral and brain histological changes coupled with impairments of glutamate synthesis, all suggestive of neurological dysfunction (Shanti et al 2004). …”

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. The results of our current study therefore present a mechanism by which vitamin D insufficiency confers risk of schizophrenia; via reduced PRODH expression, proline elevation, and the concomitant dysregulation of neurotransmission.…”

“…The proline dehydrogenase gene ( PRODH ), located within the common deleted region, encodes the PRODH/proline oxidase (POX) enzyme that catalyzes the first step in proline catabolism (see Supplementary Data, Figure S1). Proline is a neuromodulator at glutamatergic synapses (reviewed in Phang et al, 2001) and in humans the peripheral hyperprolinemia that can arise from mutations in PRODH , and which likely reflects CNS hyperprolinemia (Gogos et al, 1999; Paterlini et al, 2005; Dingman and Sporn, 1959; Efrom, 1965; Baxter et al, 1985; Jacquet et al, 2003; Shanti et al, 2004), has been significantly associated with cognitive impairment and decreased IQ (Raux et al, 2007), schizoaffective disorder (Jacquet et al, 2005) and schizophrenia (Clelland et al, 2011; Orešič et al, 2011). …”

Alanine metabolism, transport, and cycling in the brain

“…and alanine aminotransferase (ALT EC 2.6.1.2.) were isolated (Desai Shanti et al. 2004) and the activity assays performed using Infinity AST or ALT liquid assays (Thermo Electron Corporation, Vic, Australia) in the absence (control) or presence of 10 mmol/L cLeu ( n = 4).…”