Fingolimod Administration Following Hypoxia Induced Neonatal Seizure Can Restore Impaired Long-term Potentiation and Memory Performance in Adult Rats.

Neonatal seizures commonly caused by hypoxia can lead to long-term neurological outcomes. Early inflammation plays an important role in the pathology of these outcomes. Therefore, in the current study, we explored the long-term effects of Fingolimod (FTY720), an analog of sphingosine and potent sphingosine 1-phosphate (S1P) receptors modulator, as an anti-inflammatory and neuroprotective agent in attenuating anxiety, memory impairment, and possible alterations in gene expression of hippocampal inhibitory and excitatory receptors following hypoxia-induced neonatal seizure (HINS). Seizure was induced in 24 male and female pups (6 in each experimental group) at postnatal day 10 (P10) by premixed gas (5% oxygen/ 95% nitrogen) in a hypoxic chamber for 15 minutes. Sixty minutes after the onset of hypoxia, FTY720 (0.3 mg/kg) or saline (100 µl) was administered for 12 days (from P10 up to P21). Anxiety-like behavior and hippocampal memory function were assessed at P90 by elevated plus maze (EPM) and novel object recognition (NOR), respectively. Long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region (DG) following stimulation of perforant pathway (PP). In addition, the hippocampal concentration of superoxide dismutase activity (SOD), malondialdehyde (MDA), and thiol as indices of oxidative stress were evaluated. Finally, the gene expression of NR2A subunit of N-Methyl-D-aspartic acid (NMDA) receptor, GluR2 subunit of (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA receptor and γ2 subunit of γ-Aminobutyric acid (GABAA) receptor were assessed at P90 by the quantitative real-time PCR. FTY720 significantly reduced later-life anxiety-like behavior, ameliorated object recognition memory and increased the amplitude and slope of the field excitatory postsynaptic potential (fEPSP) in the rats following HINS. These effects were associated with restoration of the hippocampal thiol content to the normal values and the regulatory role of FTY720 in the expression of hippocampal GABA and glutamate receptors subunits. In conclusion, FTY720 could restore the dysregulated gene expression of excitatory and inhibitory receptors. It also increased the reduced hippocampal thiol content, which was accompanied with attenuation of HINS-induced anxiety, reduced the impaired hippocampal related memory, and prevented hippocampal LTP deficits in later life following HINS.

Maternal Morphine Exposure and Post-Weaning Social Isolation Impair Memory and Ventral Striatum Dopamine System in Male Offspring: Is an Enriched Environment Beneficial?

Maternal opioids abuse has some deleterious consequences on next generations. Besides, children's rearing conditions can affect the behavioral states and brain plasticity in their later life. In the present study, we investigated the effects of maternal morphine (MOR) treatment and post-weaning rearing conditions on memory, pain threshold, and the ventral striatum dopaminergic activity in male offspring. Female Wistar rats were treated twice daily either with escalating doses of MOR or with normal saline (NS) one week before mating, during pregnancy and lactation. After weaning, the male pups were assigned to six groups and then raised for an 8-week period under three different conditions: standard (STD), isolated (ISO) or enriched environment (EE). The behavioral tests, including passive avoidance task, novel object recognition, and tail-flick test, were also performed. Moreover, the ventral striatum dopamine's content (DA), mRNA expressions of dopamine receptor 1(D1R) and dopamine receptor 2 (D2R), and dopamine transporter (DAT) were evaluated. The obtained data showed that maternal MOR exposure and post-weaning social isolation could dramatically impair memory in offspring, while EE could reverse these adverse outcomes. Moreover, results of tail flick latency indicated the increased pain threshold in EE animals. At molecular level, maternal MOR injections and social isolation reduced DA levels and altered expressions of D1R, D2R, and DAT within the ventral striatum of these male offspring. However, post-weaning EE partially buffered these changes. Our finding signified the effects of maternal MOR exposure and social isolation on the behaviors and neurochemistry of brain in next generation, and it also provided evidence on reversibility of these alterations following EE.

The effects of myricitrin and vitamin E against reproductive changes induced by D-galactose as an aging model in female mice: An experimental study.

BACKGROUND: Aging is accompanied by decreasing general function in the cells and tissues. D-galactose (D-gal) induces aging and plays a role in the pathogenesis of it. Myricitrin is a plant-derived antioxidant. OBJECTIVE: The present study was performed to evaluate the effects of myricitrin on antioxidant defense, sex hormone levels, uterus, and ovarian histology in D-gal-induced aging female mouse model. MATERIALS AND METHODS: In this experimental study, 72 female adult NMRI mice, weighing 30-35 gr, 3-4 months old, were randomly divided into six groups (n = 12/each): (I) Control (vehicle; normal saline), (II) D-gal at 500 mg/kg/d for 45 days, (III-V) D-gal + myricitrin-treated groups (these groups received myricitrin at 5, 10, and 20 mg/kg/d, and (VI) D-gal + 100 mg/kg/d vitamin E orally for the last 28 days. The antioxidant indices were done on the basis of colorimetric method, and sex hormone levels were measured by using enzyme-linked immunosorbent assay kits. Histological assessment of the uterus and ovaries were also evaluated. RESULTS: D-gal impaired the estrous cycle, also degenerative changes occur in the ovarian follicles and damage to the uterus and ovarian tissue occurs. In D-gal group, the level of sex hormones (p = 0.03) and the total antioxidant capacity (p = 0.002) decreased, while the level of malondialdehyde and gonadotropins increased (p = 0.03). Myricitrin at lower doses and vitamin E ameliorated the D-gal effects. CONCLUSION: These findings suggest that myricitrin at low doses can effectively prevent D-gal-induced oxidation and aging in mice. The effect of myricitrin was equivalent and sometimes better than vitamin E.