Neurobehavioral, neurochemical and synaptic plasticity perturbations during postnatal life of rats exposed to chloroquine in-utero.

Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.

Kolaviron protects against cognitive deficits and cortico-hippocampal perturbations associated with maternal deprivation in rats.

Prolonged separation of pups from their mother in early postnatal period can interfere with normal growth and development, resulting in different behavioral changes similar to features of schizophrenia in man. This study explored the cytoprotective action of kolaviron, a biflavonoid, on the prefrontal cortex and hippocampus of maternally deprived Wistar rats. Eight months old female rats were time-mated, and after delivery their pups were randomly assigned into four groups; group A received 0.5 ml of normal saline, group B received kolaviron orally (200 mg/kg/bw) on postnatal days (PND) 21-35, group C were maternally deprived on PND 9 for 24 hours, while group D were also maternally deprived on PND 9 for 24 hours, and then received kolaviron orally (200 mg/kg/bw) on PND 21-35. Behavioral studies (open field test, Morris water test, and Y-maze test) were conducted after the experiment prior to sacrifice. Some of the rats were anesthetized with ketamine and perfusion-fixed with 0.1 M phosphate buffered saline and 4% paraformaldehyde, while others were sacrificed by cervical dislocation for enzyme studies. The hippocampus and prefrontal cortex were excised from the brain and processed for tissue histology, histochemistry, and enzymatic analysis. Results revealed behavioral deficits, oxidative stress, degenerative changes, and astrocytosis in the prefrontal cortex and hippocampus of maternally deprived rats, but intervention with kolaviron caused significant improvement in neurobehavior, morphology, and neurochemistry in these brain areas. We concluded that kolaviron could protect the brain against neurological consequences of nutritional and environmental insults arising from maternal separation in early postnatal period.