Pleiotropic effects of 5-aminolevulinic acid in mouse brain

Abstract

5-Aminolevulinic acid (ALA) seems to be responsible for the neuropsychiatric manifestations of acute intermittent porphyria (AIP). Our aim was to study the effect of ALA on the different metabolic pathways in the mouse brain to enhance our knowledge about the action of this heme precursor on the central nervous system. Heme metabolism, the cholinergic system, the defense enzyme system, and nitric oxide metabolism were evaluated in the encephalon of CF-1 mice receiving a single (40 mg/kg body mass) or multiple doses of ALA (40 mg/kg, every 48 h for 14 days). We subsequently found ALA accumulation in the encephalon of the mice. ALA also altered the brain cholinergic system. After one dose of ALA, a decrease in superoxide dismutase activity and a reduction in glutathione levels were detected, whereas malondialdehyde levels and catalase activity were increased. Heme oxygenase was also increased as an antioxidant response to protect the encephalon against injury. All nitric oxide synthase isoforms were induced by ALA, these changes were more significant for the inducible isoform in glial cells. In conclusion, ALA affected several metabolic pathways in mouse encephalon. Data indicate that a rapid response to oxidative stress was developed; however, with long-term intoxication, the redox balance was probably restored, thereby minimizing oxidative damage.

Systematically Analyzing the Pathogenic Variations for Acute Intermittent Porphyria

“…One of the hypotheses is the structural similarity between ALA and γ-aminobutyric acid (GABA), the accumulation of ALA may affect normal GABA function in the nervous system (Windebank and Mcdonald, 2005; Tracy and Dyck, 2014). The excess of ALA leads to the pronounced HO (heme oxygenase) activity, resulting in deregulation of the cholinergic system, increasing oxidative stress, affecting activity and expression of NOS (nitric oxide synthases) (Lavandera et al, 2016), decreasing GABAergic neurons’ activity (Brennan and Cantrill, 1979) and increasing glutamate release (Satoh et al, 2008; Duque-Serrano et al, 2018).…”

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

“…When incubated with high ALA concentrations (4.0 mM), rat cerebral cortex particles accumulate ALA intracellularly and ALAD activity is enhanced, while HMBS acts as a secondary control step, leading to a build-up of PBG [ 32 , 33 ]. More recently, in mice receiving ALA intraperitoneally, ALA accumulation in the encephalon was demonstrated, together with a plethora of effects on brain metabolism (a reduction of brain ALAS mRNA levels, an increase in cerebellar and hippocampal heme oxygenase activity, an increase in acetylcholinesterase activity, and alterations in factors involved in the management of oxidative stress) [ 34 ].…”

“…In vivo, it seems to be unaffected by fasting, ethanol, AIA, DDC, or barbiturates [ 66 , 68 , 69 ], whereas it decreases after the administration of cycloheximide or large doses of ALA, or its methyl ester [ 67 ]. In fact, brain ALAS mRNA levels in mice were shown to diminish following a chronic or acute intraperitoneal administration of ALA [ 34 ]. Notably, injected hematin and CoCl 2 are not taken up by the brain in vivo and do not affect brain ALAS activity, contrary to the liver isoform [ 67 ].…”

“…Griseofulvin is a well-known inducer of APAs and heme depletion [ 30 , 31 ]. Direct ALA administration has also been extensively utilized as a resource to study AHP in vitro and in vivo [ 32 , 33 , 34 , 35 ].…”

Therapeutic strategies for acute intermittent porphyria

“…Involvement of the CNS manifests as a combination of seizures, syndrome of inappropriate antidiuretic hormone (SIADH), posterior reversible encephalopathy syndrome (PRES), or psychiatric symptoms (agitation, hallucinations, anxiety, and depressive behaviors) (36,37). Overproduction of ALA via neurotoxicity, oxidative damage, modification of glutamatergic release, and increased metabolites of the kynurenine pathway initiates dysfunction of the CNS as mentioned above (38)(39)(40)(41). Moreover, the accumulation of ALA is assumed to impair normal γ-aminobutyric acid (GABA) function, leading to seizures and psychiatric symptoms (42)(43)(44)(45).…”