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The role of nitric oxide in glutaric acid-induced convulsive behavior in pup rats
César Augusto Brüning1, Suzan Gonçalves Rosa2, Caroline Brandão Quines2
1Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Neurobiotechnology Research Group, Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center for Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Pelotas, Brazil.
Insights
Nitric oxide (NO) contributes to seizures in Glutaric acidaemia type I (GA-I). Inhibiting NO synthesis reduced seizure duration and increased latency in rats, suggesting NO as a therapeutic target for this organic acidemia.
Area of Science:
- Neuroscience
- Biochemistry
- Pediatric Organic Acidemias
Background:
- Glutaric acidaemia type I (GA-I) is a rare metabolic disorder causing neurological damage and seizures due to glutaric acid accumulation.
- The precise mechanisms underlying GA-I-induced seizures are not fully understood, necessitating further investigation.
- Nitric oxide (NO) is implicated in various neurological processes, including seizure activity.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in glutaric acid (GA)-induced seizures in a rat model of Glutaric acidaemia type I (GA-I).
- To explore potential therapeutic strategies targeting NO pathways for managing neurological symptoms in GA-I.
Main Methods:
- Intrastriatal administration of glutaric acid (GA) to 21-day-old male Wistar rats to induce seizures.
- Administration of N-G-nitro-l-arginine methyl ester (L-NAME), a NO synthesis inhibitor, or saline (vehicle) prior to GA injection.
- Measurement of seizure latency and duration, and analysis of striatal nitrate and nitrite (NOx) levels.
Main Results:
- L-NAME significantly increased seizure latency and decreased seizure duration in GA-treated rats.
- GA administration elevated striatal NOx levels, an effect attenuated by L-NAME pretreatment.
- The NO precursor, l-arginine (L-ARG), reversed the effects of L-NAME, confirming NO's involvement.
Conclusions:
- Nitric oxide (NO) plays a significant role in the pathogenesis of glutaric acid-induced seizures in young rats.
- These findings provide experimental evidence supporting NO's contribution to the neurological manifestations of Glutaric acidaemia type I.
- Targeting NO pathways may offer a novel therapeutic approach for managing seizures in GA-I patients.
Abstract:
Glutaric acidaemia type I (GA-I) is a cerebral organic disorder characterized by the accumulation of glutaric acid (GA) and seizures. As seizures are precipitated in children with GA-I and the mechanisms underlying this disorder are not well established, we decided to investigate the role of nitric oxide (NO) in GA-induced convulsive behaviour in pup rats. Pup male Wistar rats (18-day-old) were anesthetized and placed in stereotaxic apparatus for cannula insertion into the striatum for injection of GA. The experiments were performed 3 days after surgery (pup rats 21-day-old). An inhibitor of NO synthesis (N-G-nitro-l-arginine methyl ester-L-NAME, 40 mg/kg) or saline (vehicle) was administered intraperitoneally 30 min before the intrastriatal injection of GA (1 µl, 1.3 µmol/striatum) or saline. Immediately after the intrastriatal injections, the latency and duration of seizures were recorded for 20 min. The administration of L-NAME significantly increased the latency to the first seizure episode and reduced the duration of seizures induced by GA in pup rats. The administration of the NO precursor l-arginine (L-ARG; 80 mg/kg) prevented the effects of L-NAME. Besides, GA significantly increased nitrate and nitrite (NOx) levels in the striatum of pup rats and the preadministration of L-NAME prevented this alteration. L-ARG blocked the reduction of striatal NOx provoked by L-NAME. These results are experimental evidence that NO plays a role in the seizures induced by GA in pup rats, being valuable in understanding the physiopathology of neurological signs observed in children with this organic acidaemia and to develop new therapeutic strategies.
