Effects of pyridoxine deficiency and DL-p-chlorophenylalanine administration to rats on 5-hydroxytryptamine and noradrenaline concentrations in brain and 5-hydroxytryptamine concentration in blood.
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ABSTRACT:
SUBMITTER: Bhagavan HN
PROVIDER: S-EPMC1177873 | biostudies-other | 1973 Jul
REPOSITORIES: biostudies-other
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Project description:Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene ALDH7A1 leading to recurrent neonatal seizures, which are uniquely alleviated by high doses of pyridoxine or pyridoxal 5'-phosphate (vitamin B6 vitamers). Despite treatment, neurodevelopmental disabilities are still observed in most PDE patients underlining the need for adjunct therapies. Over 60 years after the initial description of PDE, we report the first animal model for this disease: an aldh7a1-null zebrafish (Danio rerio) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 days postfertilization). Epileptiform electrographic activity was observed uniquely in mutants as a series of population bursts in tectal recordings. Remarkably, as is the case in human PDE, the seizures show an almost immediate sensitivity to pyridoxine and pyridoxal 5'-phosphate, with a resulting extension of the life span. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of aldh7a1 knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency, and low ?-aminobutyric acid levels were observed in the aldh7a1-/- larvae, which may play a significant role in the seizure phenotype and PDE pathogenesis. This novel model provides valuable insights into PDE pathophysiology; further research may offer new opportunities for drug discovery to control seizure activity and improve neurodevelopmental outcomes for PDE.
| S-EPMC5714462 | biostudies-literature
Project description:Vascular cognitive impairment (VCI) has been one of the major types of cognitive impairment. Blood-brain barrier damage plays an essential part in the pathogenesis of VCI. At present, the treatment of VCI is mainly focused on prevention, with no drug clinically approved for the treatment of VCI. This study aimed to investigate the effects of DL-3-n-butylphthalide (NBP) on VCI rats. A modified bilateral common carotid artery occlusion (mBCCAO) model was applied to mimic VCI. The feasibility of the mBCCAO model was verified by laser Doppler, 13N-Ammonia-Positron Emission Computed Tomography (PET), and Morris Water Maze. Subsequently, the Morris water maze experiment, Evans blue staining, and western blot of tight junction protein were performed to evaluate the effect of different doses of NBP (40 mg/kg, 80 mg/kg) on the improvement of cognitive impairment and BBB disruption induced by mBCCAO. Immunofluorescence was employed to examine the changes in pericyte coverage in the mBCCAO model and the effect of NBP on pericyte coverage was preliminarily explored. mBCCAO surgery led to obvious cognitive impairment and the decrease of whole cerebral blood flow, among which the blood flow in the cortex, hippocampus and thalamus brain regions decreased more significantly. High-dose NBP (80 mg/kg) improved long-term cognitive function in mBCCAO rats, alleviated Evans blue leakage and reduced the loss of tight junction proteins (ZO-1, Claudin-5) in the early course of the disease, thereby exerting a protective effect on the blood-brain barrier. No significant changes in pericyte coverage were observed after mBCCAO. High-dose NBP improved cognitive function in mBCCAO rats. High-dose NBP protected the integrity of BBB by upregulating TJ protein expression, rather than regulating pericyte coverage ratio. NBP could be a potential drug for the treatment of VCI.
| S-EPMC10567816 | biostudies-literature
Project description:Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-alpha-aminoadipic semialdehyde/L-Delta1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine L-alpha-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-alpha-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.
| S-EPMC2892945 | biostudies-literature
Project description:BackgroundNorepinephrine has been suggested to regulate ethanol (EtOH)-related behaviors, but little is known about the effects of EtOH on norepinephrine release in mesocortical and mesolimbic brain areas that are targets of EtOH actions.MethodsWe used in vivo microdialysis to examine the effects of EtOH on extracellular norepinephrine concentrations in mesocorticolimbic brain regions of male Long Evans rats. We determined the effects of intravenous infusion of saline or EtOH in the medial prefrontal cortex (mPFC) and the basal forebrain. We also measured dialysate norepinephrine concentrations during operant self-administration of EtOH in the mPFC.ResultsIntravenous infusion (1 or 0.25 ml/min) of 1.0 g/kg EtOH stimulated an increase in dialysate norepinephrine in mPFC and in basal forebrain. In the basal forebrain, an infusion of 0.5 g/kg EtOH did not stimulate dialysate norepinephrine concentrations. In both regions, saline infusions did not increase dialysate norepinephrine concentrations. In the behavioral experiment, 1 week of experience with operant self-administration of sweetened EtOH resulted in an apparent reduction in basal dialysate norepinephrine concentrations in the mPFC relative to the sucrose control. Dialysate norepinephrine increased during the transfer from home cage to the operant chamber in all groups.ConclusionsWe conclude that acute EtOH stimulates both the locus coeruleus (which projects to the mPFC) and the nucleus tractus solitarius (which projects to the basal forebrain) noradrenergic neurons. Additionally, limited EtOH self-administration experience alters dialysate norepinephrine in the mPFC in a manner consistent with a decrease in tonic norepinephrine release. Further studies are necessary to elucidate the mechanisms by which EtOH exerts these variable effects.
| S-EPMC7556343 | biostudies-literature
Project description:BackgroundCannabis availability with high concentrations of ?-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations.MethodsIn adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain.ResultsBlood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD + THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0-11 ng/mL; CBD: 9.7-19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD + THC.ConclusionsIn adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.
| S-EPMC7371526 | biostudies-literature
Project description:BackgroundDBS are an increasingly common clinical matrix.Methods & resultsSensitive and specific methods for DBS and venous blood cocaine and metabolite detection by LC-HRMS and 2D GC-MS, respectively, were validated to examine correlation between concentrations following controlled intravenous cocaine administration. Linear ranges from 1 to 200 µg/l were achieved, with acceptable bias and imprecision. Authentic matched specimens' (392 DBS, 97 venous blood) cocaine and benzoylecgonine concentrations were qualitatively similar, but DBS had much greater variability (21.4-105.9 %CV) and were lower than in blood.ConclusionDBS offer advantages for monitoring cocaine intake; however, differences between capillary and venous blood and DBS concentration variability must be addressed.
| S-EPMC4644129 | biostudies-literature
Project description:BACKGROUND:Although it has been purported that HIV-positive individuals may experience a greater degree of intoxication than HIV-negative individuals following acute alcohol consumption, no research to date has empirically tested this supposition. The present investigation entailed a randomized controlled experiment to identify whether the administration of a weight-specified dose of alcohol would lead to differential blood alcohol concentrations (BACs) among HIV-positive versus HIV-negative men. METHODS:In a specialized barroom laboratory, 143 men (n = 76 HIV-positive and n = 67 HIV-negative; mean age = 42.9) consumed beverages based on a formulation of 0.7 g alcohol/kg body weight over a 15-minute time frame. BAC was assessed via breathalyzer at 2 set time points (10 and 13 minutes postconsumption) and then periodically until detoxification (BAC < 0.040%). Primary outcomes included (i) area under the curve (AUC), calculated based on all of one's BAC readings, (ii) "BAC-EXP," defined as one's BAC reading 13 minutes postconsumption, and (iii) BAC-PEAK, defined as one's highest recorded BAC reading. RESULTS:Contrary to predictions, AUC (t(141) = 2.23, p = 0.027), BAC-EXP (t(141) = 2.68, p = 0.008), and BAC-PEAK (t(141) = 2.29, p = 0.023) were significantly lower among HIV-positive versus HIV-negative participants. These effects were sustained in multivariable models controlling for age, race, and AUDIT-based hazardous drinking classification. Among the HIV-positive sample, outcomes did not significantly differ based on HIV viral load detectability, antiretroviral therapy (ART) status, or ART adherence. CONCLUSIONS:The administration of a controlled, weight-specified dose of alcohol led to lower BACs among HIV-positive versus HIV-negative participants. These differences might derive from decreased body fat percentage and delayed gastric emptying associated with HIV seropositivity; however, additional research is necessary to verify these mechanisms. Unique alcohol dosing formulas based on HIV serostatus may be required in future alcohol administration experiments involving HIV-positive samples.
| S-EPMC6120761 | biostudies-literature
Project description:The gene expression of serotonin 5-hydroxytryptamine receptor 3A (receptor 3A:HTR3A) as well as the concentration of electrolytes in male Wistar rats after administration of graded doses of marijuana extract was investigated. Twelve groups (3 control and 9 test groups) of 6 animals each were daily exposed to 12.5, 25 and 50 mg/kg b.w doses of petroleum ether extract of marijuana for 4, 8 and 12 weeks. The expressions of the gene were obtained using reverse transcriptase-polymerase chain reaction (RT-PCR) while electrolytes concentrations were determined. An upregulation of over 90% was observed in the expression of HTR3A after exposure to the highest dose throughout the exposure period. There was significant increase in the plasma potassium concentration at all doses while there was a decrease in the brain only at 50 mg/kg dose throughout the exposure period. Sodium concentration in the brain was not affected by the doses over the period of exposure but plasma concentration decreased significantly. All the doses of marijuana extract significantly increased calcium concentration in the brain after prolonged exposure but the plasma concentration remained unchanged. This suggests that different doses of marijuana extract alter the expression of serotonin receptor and electrolyte concentrations over a period of time with possible neurological consequences.
| S-EPMC7936388 | biostudies-literature
Project description:Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of the lysine catabolism pathway. PDE is characterized by recurrent seizures that are resistant to conventional anticonvulsant treatment but are well-controlled by pyridoxine (PN). Most PDE patients also suffer from neurodevelopmental deficits despite adequate seizure control with PN. To investigate potential pathophysiological mechanisms associated with ALDH7A1 deficiency, we generated a transgenic mouse strain with constitutive genetic ablation of Aldh7a1. We undertook extensive biochemical characterization of Aldh7a1-KO mice consuming a low lysine/high PN diet. Results showed that KO mice accumulated high concentrations of upstream lysine metabolites including ∆1-piperideine-6-carboxylic acid (P6C), α-aminoadipic semialdehyde (α-AASA) and pipecolic acid both in brain and liver tissues, similar to the biochemical picture in ALDH7A1-deficient patients. We also observed preliminary evidence of a widely deranged amino acid profile and increased levels of methionine sulfoxide, an oxidative stress biomarker, in the brains of KO mice, suggesting that increased oxidative stress may be a novel pathobiochemical mechanism in ALDH7A1 deficiency. KO mice lacked epileptic seizures when fed a low lysine/high PN diet. Switching mice to a high lysine/low PN diet led to vigorous seizures and a quick death in KO mice. Treatment with PN controlled seizures and improved survival of high-lysine/low PN fed KO mice. This study expands the spectrum of biochemical abnormalities that may be associated with ALDH7A1 deficiency and provides a proof-of-concept for the utility of the model to study PDE pathophysiology and to test new therapeutics.
| S-EPMC7689292 | biostudies-literature
Project description:There has been an unprecedented interest in the modulatory effects of intranasal oxytocin on human social cognition and behaviour, however as yet no study has actually demonstrated that this modality of administration increases concentrations of the peptide in the brain as well as blood in humans. Here using combined blood and cerebrospinal fluid (CSF) sampling in subjects receiving either 24 IU of oxytocin (n = 11) or placebo (n = 4) we have shown that oxytocin levels significantly increased in both plasma and CSF. However, whereas oxytocin plasma concentrations peaked at 15 min after intranasal administration and decreased after 75 min, CSF concentrations took up to 75 min to reach a significant level. Moreover, there was no correlation (r = <0.10) between oxytocin plasma and CSF concentrations. Together, these data provide crucial insights into the plasma and CSF kinetics of intranasally administered oxytocin.
| S-EPMC3853684 | biostudies-other