δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [<sup>14</sup>C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

Percy, V. A.; Lamm, M. C. L.; Taljaard, J. J. F.

doi:10.1111/j.1471-4159.1981.tb02378.x

Cited by 36 publications

(9 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indirect mechanisms have also been postulated (Opler et al, 2004), including renal damage (Loghman-Adham, 1997), effects on transthyreitin secretion in the choroid plexus (Zheng et al, 1999), and interactions with nutrient absorption. It is also possible, as noted previously (Opler et al, 2004), that d-ALA could increase schizophrenia risk through neurotoxic effects on GABA neurotransmission (Percy et al, 1981). …”

Section: Risk Factor Studies Of Schizophreniamentioning

confidence: 66%

The environment and susceptibility to schizophrenia

Brown

2011

Progress in Neurobiology

568

411

View full text Add to dashboard Cite

In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban–rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections [e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2)], nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures [e.g. lead, rhesus (Rh) incompatibility, maternal stress]. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and more rigorous epidemiologic investigations, and research on translational and clinical neuroscience, gene–environment interactions, epigenetics, developmental trajectories and windows of vulnerability, are elaborated upon. These studies are aimed at confirming observed risk factors, identifying new environmental exposures, elucidating developmental mechanisms, and shedding further light on genes and exposures that may not be identified in the absence of these integrated approaches. The study of environmental factors in schizophrenia may have important implications for the identification of causes and prevention of this disorder, and offers the potential to complement, and refine, existing efforts on explanatory neurodevelopmental models.

show abstract

Section: Risk Factor Studies Of Schizophreniamentioning

confidence: 66%

The environment and susceptibility to schizophrenia

Brown

2011

Progress in Neurobiology

568

411

View full text Add to dashboard Cite

show abstract

“…Previously, a number of in vitro and in vivo studies have demonstrated the neurotoxicity of ALA mediated by effects on the GABAergic system [ 36 , 37 , 38 ]. However, this involvement was not entirely clear since some studies found slight and questionable effects [ 39 , 40 ], while other studies showed effects only at high concentrations of ALA [ 41 , 42 ], which would not normally be found in CNS diseases [ 36 ]. Despite the fact that ALA is an analogue to the neurotransmitter γ-aminobutyric acid (GABA), Emanueli et al .…”

Section: Discussionmentioning

confidence: 99%

Are Delta-Aminolevulinate Dehydratase Inhibition and Metal Concentrations Additional Factors for the Age-Related Cognitive Decline?

Baierle

Charão

Göethel

et al. 2014

IJERPH

View full text Add to dashboard Cite

Aging is often accompanied by cognitive impairments and influenced by oxidative status and chemical imbalances. Thus, this study was conducted to examine whether age-related cognitive deficit is associated with oxidative damage, especially with inhibition of the enzyme delta-aminolevulinate dehydratase (ALA-D), as well as to verify the influence of some metals in the enzyme activity and cognitive performance. Blood ALA-D activity, essential (Fe, Zn, Cu, Se) and non-essential metals (Pb, Cd, Hg, As, Cr, Ni, V) were measured in 50 elderly and 20 healthy young subjects. Cognitive function was assessed by tests from Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery and other. The elderly group presented decreased ALA-D activity compared to the young group. The index of ALA-D reactivation was similar to both study groups, but negatively associated with metals. The mean levels of essential metals were within the reference values, while the most toxic metals were above them in both groups. Cognitive function impairments were observed in elderly group and were associated with decreased ALA-D activity, with lower levels of Se and higher levels of toxic metals (Hg and V). Results suggest that the reduced ALA-D activity in elderly can be an additional factor involved in cognitive decline, since its inhibition throughout life could lead to accumulation of the neurotoxic compound ALA. Toxic metals were found to contribute to cognitive decline and also to influence ALA-D reactivation.

show abstract

“…These diseases are accompanied by a variety of neuropsychiatric symptoms (Brennan and Cantrill, 1979), and it has been suggested that these symptoms arise from the accumulation of the porphyrin precursors 5‐ALA and/or porphobilinogen (Yeung et al, 1987). 5‐ALA may be directly neurotoxic (Percy et al, 1981 ; Russell et al, 1983), and it may modulate CNS signal transduction by being an agonist for presynaptic GABA autoreceptors (Brennan and Cantrill, 1979). 5‐ALA has also been used clinically to delineate malignant gliomas (Stummer et al, 1998 c ).…”

mentioning

confidence: 99%

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

Novotny¹,

Xiang²,

Stummer³

et al. 2000

Journal of Neurochemistry

104

View full text Add to dashboard Cite

5-Aminolevulinic acid (5-ALA) is a precursor of porphyrins and heme that has been implicated in the neuropsychiatric symptoms associated with porphyrias. It is also being used clinically to delineate malignant gliomas. The blood-CSF barrier may be an important interface for 5-ALA transport between blood and brain as in vivo studies have indicated 5-ALA is taken up by the choroid plexuses whereas the normal blood-brain barrier appears to be relatively impermeable. This study examines the mechanisms of 5-[ 3 H]ALA uptake into isolated rat lateral ventricle choroid plexuses. Results suggest that there are two uptake mechanisms. The first was a Na ϩ -independent uptake system that was pH dependent (being stimulated at low pH). Uptake was inhibited by the dipeptide Gly-Gly and by cefadroxil, an ␣-amino-containing cephalosporin. These properties are the same as the proton-dependent peptide transporters PEPT1 and PEPT2, which have recently been shown to transport 5-ALA in frog oocyte expression experiments. Choroid plexus uptake was not inhibited by captopril, a PEPT1 inhibitor, suggesting PEPT2-mediated uptake. The presence of PEPT2 and absence of PEPT1 in the choroid plexus were confirmed by western blotting. The second potential mechanism was both Na ϩ and HCO 3 Ϫ dependent and appears to be an organic anion transporter, although it is possible that removal of Na ϩ and HCO 3 Ϫ may indirectly affect PEPT2 by affecting intracellular pH. The presence of PEPT2 and a putative Na ϩ /HCO 3 Ϫ -dependent organic anion transporter is important not only for an understanding of 5-ALA movement between blood and brain but also because these transporters may affect the distribution of a number of drugs between blood and CSF.

show abstract

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [¹⁴C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

Cited by 36 publications

References 31 publications

The environment and susceptibility to schizophrenia

The environment and susceptibility to schizophrenia

Are Delta-Aminolevulinate Dehydratase Inhibition and Metal Concentrations Additional Factors for the Age-Related Cognitive Decline?

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

Contact Info

Product

Resources

About

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [14C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture

Cited by 36 publications

References 31 publications

The environment and susceptibility to schizophrenia

The environment and susceptibility to schizophrenia

Are Delta-Aminolevulinate Dehydratase Inhibition and Metal Concentrations Additional Factors for the Age-Related Cognitive Decline?

Mechanisms of 5‐Aminolevulinic Acid Uptake at the Choroid Plexus

Contact Info

Product

Resources

About

δ‐Aminolaevulinic Acid Uptake, Toxicity, and Effect on [¹⁴C]γ‐Aminobutyric Acid Uptake into Neurons and Glia in Culture