A Dual Effect of Dopamine on Hippocampal LTP and Cognitive Functions in Control and Kindled Mice.

The impact of dopamine on synaptic plasticity and cognitive function following seizure is not well understood. Here, using optogenetics in the freely behaving animal, we examined exploratory behavior and short-term memory in control and kindled male mice during tonic stimulation of dopaminergic neurons within the ventral tegmental area (VTA). Furthermore, using field potential recording, we compared the effect of dopamine on synaptic plasticity in stratum radiatum and stratum oriens layers of both ventral and dorsal hippocampal CA1 regions, and again in both control and kindled male mice. Our results demonstrate that tonic stimulation of VTA dopaminergic neurons enhances novelty-driven exploration and short-term spatial memory in kindled mice, essentially rescuing the seizure-induced cognitive impairment. In addition, we found that dopamine has a dual effect on LTP in control versus kindled mice, such that application of dopamine prevented LTP induction in slices from control mice, but rescued LTP in slices taken from the kindled animal. Taken together, our results highlight the potential for dopaminergic modulation in improving synaptic plasticity and cognitive function following seizure.

Activation of the PI3K/AKT/mTOR Pathway in Cajal-Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures.

Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro-caudal and medio-lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.

Environmental enrichment and social isolation modulate inhibitory transmission and plasticity in hippocampal area CA2.

Environmental factors are well-accepted to play a complex and interdependent role with genetic factors in learning and memory. The goal of this study was to examine how environmental conditions altered synaptic plasticity in hippocampal area CA2. To do this, we housed adult mice for 3 weeks in an enriched environment (EE) consisting of a larger cage with running wheel, and regularly changed toys, tunnels and treats. We then performed whole-cell or extracellular field recordings in hippocampal area CA2 and compared the synaptic plasticity from EE-housed mice with slices from littermate controls housed in standard environment (SE). We found that the inhibitory transmission recruited by CA3 input stimulation in CA2 was significantly less plastic in EE conditions as compared to SE following an electrical tetanus. We demonstrate that delta-opioid receptor (DOR) mediated plasticity is reduced in EE conditions by direct application of DOR agonist. We show that in EE conditions the overall levels of GABA transmission is reduced in CA2 cells by analyzing inhibition of ErbB4 receptor, spontaneous inhibitory currents and paired-pulse ratio. Furthermore, we report that the effect of EE of synaptic plasticity can be rapidly reversed by social isolation. These results demonstrate how the neurons in hippocampal area CA2 are sensitive to environment and may lead to promising therapeutic targets.

Ameliorative effect of cotreatment with the methanolic leaf extract of Urtica dioica on acute kidney injury induced by gentamicin in rats.

OBJECTIVE: Effects of cotreatment with Urtica dioica (UD) methanolic leaf extract on gentamicin (GM)-induced acute kidney injury were evaluated in rats. MATERIALS AND METHODS: Male Wistar rats (n=32) were separated into four groups. Gentamicin (100 mg/kg/day, IP) was injected for eight days with or without UD methanolic extract (200 mg/kg/day, gavage).  The renal blood flow (RBF) and systolic blood pressure of rats were recorded. Concentration of creatinine, blood urea nitrogen (BUN), sodium, and potassium and osmolarity were measured in the urine and plasma samples. Oxidative stress level was determined by assessment of the levels of antioxidant power (FRAP) and lipid peroxidation (MDA) in the renal tissue. The renal injury and histopathological changes in the kidney were determined by microscopic evaluations. RESULTS: Administration of UD extract along with GM, compared to GM group, significantly decreased the amounts of plasma creatinine and BUN, urinary sodium excretion, fractional excretion of sodium and potassium, and MDA levels but significantly increased creatinine clearance, urine osmolarity, renal blood flow and FRAP levels. CONCLUSION: The cotreatment of UD extract can attenuate renal injury of GM by reduction of oxidative stress, lipid peroxidation, and oxygen free radicals. The potential nephroprotective effects of UD extract are probably mediated via its antioxidant and anti-inflammatory activity.

Ameliorative Effects of Zataria Multiflora Hydro-Alcoholic extract on Gentamicin Induced Nephrotoxicity in Rats.

BACKGROUND: Nephrotoxicity is the major side effects of aminoglycoside antibiotics such as gentamicin. The aim of this study was to investigate the therapeutic effects of Z.multiflora (ZM) hydroalcoholic extract on gentamicin-induced nephrotoxicity. METHODS: Twenty-eight male Wistar rats categorized into four groups: 1) the control group without injection, 2) the gentamicin treated group (100 mg/kg, i.p) 3) the gentamicin and Z. Multiflora treated group; Z. Multiflora extract(0.8 mg/ml in the drinking water) administered after gentamicin (100 mg/kg, i.p) 4) the normal saline and Z. Multiflora treated group; Z. Multiflora extract (0.8 mg/ml in the drinking water) administered after normal saline injection (2 ml/kg,i.p ). RESULTS: Post-treatment with ZM extract caused a significant reduction in the levels of plasma creatinine and blood urea nitrogen (BUN), absolute and fractional excretion of sodium, malondialdehyed (MDA) level in comparison to gentamicin group. In addition, ZM extract significantly increased creatinine clearance, urine osmolarity, and Renal blood flow (RBF) and the Ferric reducing ability of plasma (FRAP) level which had decreased compared to the control group as a result of treatment with gentamicin. CONCLUSION: The above result indicated that ZM extract improved renal toxicity of gentamicin via reducing oxidative stress, oxygen-free radicals, and lipid peroxidation.

The PTZ kindling mouse model of epilepsy exhibits exploratory drive deficits and aberrant activity amongst VTA dopamine neurons in both familiar and novel space.

Recurrent seizures that define epilepsy are often accompanied by psychosocial problems and cognitive deficits with incompletely understood aetiology. We therefore used the pentylenetetrazol (PTZ) kindling model of epilepsy in mice to examine potential seizure-associated neuropathologies, focusing on motivation, memory and novel-environment-induced activation of midbrain dopaminergic neurons. In addition to recurrent seizures, we found that PTZ kindling led to a strong suppression of novelty-driven exploration while largely sparing fear-driven exploration. The deficits in exploratory drive may be relevant for other cognitive impairments since reduced unassisted rearing in a learning arena correlated with poorer spatial memory of object location. Using c-Fos immunofluorescence as a marker of neuronal activity, we observed that dopamine neurons within the ventral tegmental area (VTA) of PTZ kindled mice demonstrate hyperactivity at baseline and hypoactivity in response to a novel environment compared to saline-injected cagemate controls. These data extend previous findings of PTZ kindling-mediated disruptions of hippocampal processes important for novel environment recognition and learning by demonstrating PTZ kindling also induces motivational deficits that are associated with reduced stimulus-evoked activation of VTA dopamine neurons. More broadly, these data help understand the aetiology of complex behavioural changes in the PTZ kindling model, and may assist in the development of superior diagnoses and treatments for epilepsy.

Modulatory effect of semelil (ANGIPARS™) on isoproterenol induced cardiac injury.

Administration of semelil (ANGIPARS™) has been successful in the treatment of diabetic foot ulcer. Considering the improvement of blood flow and anti-inflammatory effect that are attributed to this drug, we investigated its effect on cardiovascular performance in rabbits with isoproterenol (ISO) induced myocardial injury. Animal groups included: control group; ISO group, received ISO 50 mg/kg s.c. for two consecutive days; S1+ISO, S5+ISO and S10+ISO groups, received semelil 1, 5, and 10 mg/kg/day i.p. respectively, 30 min before ISO. On the 3(rd) day, electrocardiogram (ECG) and hemodynamic parameters were recorded; blood samples were taken and hearts were removed for lab investigations. ISO induced heart injury, ECG disturbance, raise of cardiac troponin I and significant decrease in LVSP (p<0.05), +dp/dt max (p<0.01), -dp/dt max (p<0.05) along with increase of LVEDP (p<0.01). Semelil had no significant effects on ECG and plasma cardiac troponin I. Impairment of +dp/dt max and -dp/dt max was significantly improved in S5+ISO and S10+ISO groups (P<0.05 versus ISO). In addition, LVSP and LVEDP was somewhat recovered in these groups, although semelil (1 mg/kg/day) to some extent exacerbated the myocardial lesions induced by ISO (P<0.05). Therefore, in stressful conditions, semelil may improve myocardial contractility; however, it may aggravate the severity of injury.

Prevalence of HBsAg and high-risk behaviors in pregnant women rerring to Urban Health Centers in Isfahan province.

BACKGROUND: About 5% of the world population are carriers of the hepatitis B virus which is not the same in different areas of the world. Iran, with a rate of 2-3%, is among the countries with average prevalence. The aim of this study was to determine the prevalence of HBsAg and its associated factors in pregnant women who referred to urban health centers in Isfahan Province. METHODS: This was a descriptive study conducted on 1078 pregnant women who had referred to the urban health centers of Isfahan, Borkhar, Meymeh, Khomeini Shahr, Lenjan and Najaf Abad in 2009 in order to register their physical condition and receive pregnancy care. Random sampling method by quota was done. First, a questionnaire including demographic characteristics and history of high-risk behaviors in mothers and their husbands was completed. Then, a blood sample was taken and evaluated for the HB virus surface antigen. Finally, the data was analyzed using SPSS software, Chi-square, Fisher and Logistic Regression tests. RESULTS: HB virus surface antigen was traced in the serum of 0.5% of the participants. The average age of subjects was 26.1± 4.9 (mean±sd) years old and the average pregnancy number was 1.79 + 1.0 (mean±sd). Using Fisher's test as well as logistic regression test and based on the previous history of high-risk sexual behaviors and tattooing, a significant difference was observed between the two groups with positive and negative HBsAg (p ≤ 0.05). CONCLUSIONS: Instructing the target groups and close monitoring of the high-risk centers such as beauty shops, tattooing centers and etc, and also staff training on how to use disposable and sterilized equipments have to be accomplished at the right time.

The study of Prevalence of Antigen HBs Positive and High-risk Behaviors in Pregnant Women Referring to Urban Health Centers of Isfahan Province in 2009.

BACKGROUND: Around 5% of the world populations are the carriers of the hepatitis B virus. Prevalence of carriers in many different areas of the world is various. Iran, including the rate of 2 to 3%, is among countries, which has the average prevalence. The aim of this study was to determine the prevalence of antigen HBs positive and associated factors in pregnant women who had referred to urban health centers of Isfahan Province in 2009. METHODS: A descriptive study conducted on 1078 pregnant women who had referred to the urban health centers of Isfahan, Barkhovar, Meymeh, Khomeini Shahr, Lenjan and Najaf Abad in 2009 in order to register their physical condition and conducting pregnancy care. Random sampling method by quota was systematic. First, a questionnaire completed including demographic characteristics and records of high-risk behaviors in mothers and wives. Then, 4 cc of their blood drawn and evaluated the antigen surface in serum. Finally, the data were analyzed using SPSS15 software, Chi-square, Fisher and Logistic Regression tests. RESULTS: According to the findings, serum of 0.5% of pregnant women under the study was HBsAg-positive. The average age of subjects was 26.1 (4.9) years old and the average pregnancy number was 1.79 (1.0). Using Fisher's test as well as logistic regression test and based on the previous records of high-risk sexual behaviors and tattooing, a significant difference was observed in positive-HBsAg group in comparison with negative-HBsAg group (p ≤ 0.05). CONCLUSIONS: Instructing target groups and giving awareness in large-scale, close monitoring in high-risk centers such as beauty shops, tattooing centers and etc, and also staff training in how to use disposable and sterilized equipments have to be accomplished at the right time.