Life‐spanning Behavioural and Adrenal Dysfunction Induced by Prenatal Hypoxia in the Rat is Prevented by the Calcium Antagonist Nimodipine

Abstract

The long-term behavioural effects of prenatal chronic anaemic hypoxia were investigated in young (5 months old), late adult (19 months) and aged Wistar rats (23-26 months). Sodium nitrite (2 g/l) offered in the drinking water during the second half of pregnancy served to evoke prenatal hypoxia. In parallel to nitrite treatment the Ca2+ channel blocker nimodipine (10 mg/kg) or vehicle alone was administered intragastrically once daily. Open-field activity, intermale social behaviour, learning ability in a black-white discrimination paradigm and fear-induced emotionality were assessed at different ages. Plasma corticosterone response to novelty stress was measured by blood sampling through chronic venous canulas at the age of 28 months. The nitrite-exposed 5-month-old offspring started exploration in a novel open-field with considerable delay. This delayed start-latency was augmented in 19- and 23-month-old rats, pointing to exaggerated suppression of behavioural arousal. Nitrite-induced hypoxia decreased the duration of social interactions during ageing. Aged rats exposed to nitrite were unable to learn a black-white discrimination but showed a normal generalized conditioned fear response (immobility) to the test situation as a whole. The conditioned fear-induced vocalization was more frequent among hypoxic aged animals. The aged hypoxic rats displayed a prolonged plasma corticosterone stress response and had higher adrenal weight than their controls. The abnormal open-field, social, learning and emotional behaviours, as well as the altered plasma corticosterone response, were prevented by prenatal nimodipine treatment.

Social behavior impairment in offspring exposed to maternal seizures in utero

“…To our knowledge, few studies have investigated the social interaction following prenatal hypoxia. Corroborating our results, Nyakas et al (1994) reported that nitrite-induced hypoxia during the second half of pregnancy decreased the duration of social interactions in aged Wistar rats. Developing neurons are particularly susceptible to hypoxic-ischemic injury; however, brain damage and subsequent neurodevelopmental impairment depends on the severity, duration and repetition of the insult, as well as on the maturity and condition of the fetus (Gunn and Bennet 2009).…”

“…In fact, a number of epidemiological studies and rodent models have confirmed that hypoxic-ischemic insults disrupt normal brain development, with long-lasting behavioral, motor and cognitive implications (Tejkalova et al 2007), which represent a risk factor for mental retardation, attention-deficit/ hyperactivity disorder (ADHD), memory impairment and schizophrenia (Adriani et al 2006). In addition, there is evidence that prenatal hypoxia leads to a decrease in social contact in rats (Nyakas et al 1994). Taking all this information together, the aim of the present study was to verify the adult social behavior of offspring exposed to maternal convulsive seizures in utero.…”

Pregnancy as a valuable period for preventing hypoxia‐ischemia brain damage

“…Similar effects were observed using nimodipine (a well‐known calcium channel blocker). Oral daily administration of nimodipine (10 mg/kg) was able to prevent abnormal learning, social and emotional behavior impairments, as well as the stress response after prenatal hypoxia induced by sodium nitrate in the second half of gestation in Wistar rats suggesting that the reduction of excitotoxicity is an important pathway that could be modulated during pregnancy (Nyakas et al, 1994b).…”

“…Nimodipine is an L‐type Ca ++ channel blocker and has shown to penetrate through the placenta and consequently exert pharmacological action directly in the foetus. Nyakas et al (1994a,b) administered nimodipine in the food pellets during pregnancy and observed that the substance counteracted the anaemic‐cytotoxic hypoxia induced by sodium nitrite (2 g/l) administered in the drinking water during pregnancy. Nimodipine prevented the decrease in serotonergic and cholinergic nerve fiber growth in a region‐specific manner in the cortex as from 1 to 20 days post injury (Nyakas et al, 1994a).…”

The beneficial effects of nettle supplementation and exercise on brain lesion and memory in rat

“…The test was performed on the fifth postoperative day. Rats were positioned into the center of an open-field box consisting of a cylindrical arena of 80 cm in diameter, divided into 20 sectors by concentric and radial lines, and surrounded by a 35-cm-high wall [33]. During a 3-1min recording period, the number of lines crossed between sectors and the number and duration of rearings were scored.…”