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• Oligomeric Aβ microinjection into the EC disrupted LTP maintenance in the DG • EC amyloidopathy impaired spatial and non-spatial long term memories • PKMζ overexpression in DG rescued LTP and memory of rats with EC amyloidopathy • Zeta inhibitory peptide blocked the improving effect of PKMζ on LTP and memory Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (Aβ) impair synaptic transmission in experimental AD models. Protein kinase Mζ (PKMζ) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKMζ overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric Aβ 1-42 (oAβ) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 µL of lentiviral vector (~108 TU/mL) encoding PKMζ genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKMζ overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKMζ ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKMζ inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKMζ on synaptic activity and memory performance. PKMζ-dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD. [ABSTRACT FROM AUTHOR]

At early stages of Alzheimer's disease (AD), soluble amyloid beta (Aβ) accumulates in brain while microglia are in resting state. Microglia can recognize Aβ long after formation of plaques and release neurotoxic mediators. We examined impact of early minor activation of microglia by Toll-like receptors (TLRs) 2 and 4 agonists on Alzheimer's disease-related disturbed synaptic function and spatial memory in rats. Microglial BV-2 cells were treated by 0.1, 1, and 10 μg/mL of the TLRs ligands lipopolysaccharide, monophosphoryl lipid A (MPL), and Pam3Cys for 24 hours. Culture medium was then changed with media containing 1-μM Aβ. Tumour necrosis factor (TNF)-α and CCL3 levels were measured in the supernatant, 24 hours thereafter. One μg of TLRs ligands which was able to release low level of TNF-α and CCL3, was administered intracerebroventricularly (i.c.v) to adult male rats every 3 days for 24 days. At the half of the treatment period, Aβ1-42 was infused i.c.v (0.075 μg/hour) for 2 weeks. Finally, the following factors were measured: memory performance by Morris water maze, postsynaptic potentials of dentate gyrus following perforant pathway stimulation, hippocampal inflammatory cytokines interleukin 1 (IL-1)β and TNF-α, anti-inflammatory cytokines IL-10 and TGF-1β, microglia marker arginase 1, Aβ deposits, and the receptor involved in Aβ clearance, formyl peptide receptor 2 (FPR2). TLRs ligands caused dose-dependent release of TNF-α and CCL3 by BV-2 cells. Aβ-treated cells did not release TNF-α and CCL3, whereas those pretreated with MPL and Pam3Cys significantly released these cytokines in response to Aβ. Low-dose TLRs ligands improved the disturbance in spatial and working memory; restored the impaired long-term potentiation induced by Aβ; decreased TNF-α, and Aβ deposits; enhanced TGF-1β, IL-10, and arginase 1 in the hippocampus of Aβ-treated rats; and increased polarization of hippocampal microglia to the anti-inflammatory phenotype. The ligands increased formyl peptide receptor 2 in both BV-2 cells and hippocampus/cortex of Aβ-treated rats. Microglia can sense/clear soluble Aβ by early low-dose MPL and Pam3Cys and safeguard synaptic function and memory in rats. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Identification of key molecular changes occurring during epileptogenesis provides better understanding of epilepsy and helps to develop strategies to modify those changes and thus, block the epileptogenic process. Gap junctional communication is thought to be involved in epileptogenesis. This communication can be affected by changes in expression of gap junctional protein subunits called connexins (Cxs). One of the main brain regions involved in epileptogenesis is the hippocampus in which there is a network of gap junctional communication between different cell types. Method: Cx36 and Cx43 expressions at both mRNA and protein level were measured in rat hippocampus during epileptogenesis in the kindling model of epilepsy. Results: Cx36 expression at both mRNA and protein level was upregulated during acquisition of focal seizures but returned to basal level after acquisition of secondarily-generalized seizures. No change in Cx43 gene and protein expression was found during kindling epileptogenesis. Conclusion: These results further point out the significance of Cx36 as a target to modify epileptogenic process and to develop antiepileptogenic treatments. [Copyright &y& Elsevier]

Abstract: Background: Based on a traditional belief, Echium amoenum (Boraginaceae) dried flowers are used in Iran as an anxiolytic remedy and also as a mood enhancer. In this study, efficacy of an aqueous extract of E. amoenum in patients with mild to moderate major depressive disorder (a score ≥18 on the Hamilton depression rating scale) was evaluated. Methods: 35 patients were randomly assigned to receive daily either placebo or 375 mg of E. amoenum aqueous extract in a 6-week double blind, parallel-group trial. Patients were assessed in weeks 0, 1, 2, 4 and 6 by the Hamilton Rating Scale for Depression (HAM-D17), the Hamilton Rating Scale for Anxiety (HAM-A14), and a score sheet on adverse effects. Results: In week 4, the extract showed a significant superiority over placebo in reducing depressive symptoms. The effect on anxiety was not significant. Headache, somnolence, vomiting, dry mouth, constipation and blurred vision are the most commonly reported side effects. However, with regards to these side effects, no significant difference between placebo and drug treated groups was observed. Limitations: This study is performed with a small sample size, only with one dose and for 6 weeks. Conclusion: E. amoenum aqueous extract may have some antidepressant activity. [Copyright &y& Elsevier]

Artemisia dracunculus L. (Asteraceae) has been used orally as an antiepileptic remedy in Iranian folkloric medicine. The anticonvulsant potential and composition of the essential oil obtained from the aerial parts of the plant were assessed in this study. The essential oil exerted dose- and time-dependent antiseizure activity in both maximal electroshock (MES) and pentylenetetrazole models of experimental seizures with ED50 values of 0.84 and 0.26ml/kg, respectively. At some anticonvulsant doses, the essential oil produced sedation and motor impairment assessed by rotarod test. Gas chromatography (GC)/mass spectrometry (MS) analysis of the essential oil revealed the presence of trans-anethole (21.1%), α-trans-ocimene (20.6%), limonene (12.4%), α-pinene (5.1%), allo ocimene (4.8%), methyl eugenol (2.2%), β-pinene (0.8%), α-terpinolene (0.5%), bornyl acetate (0.5%) and bicyclogermacrene (0.5%) as the main components. The observed anticonvulsant and sedative effects could be related to the presence of monoterpenoids in the essential oil. [Copyright &y& Elsevier]

Lactuca sativa (Lettuce) is a member of Compositae family. In folk medicine of Iran, the seeds of this plant were used for relieving of inflammation and osteodynia. In this study, anti-nociceptive and anti-inflammatory activities of a crude methanol/petroleum ether (70/30, v/v) extract of the seeds have been evaluated. The extract exhibited a time- and dose-dependent analgesic effect in formalin test and also a dose-dependent anti-inflammatory activity in a carrageenan model of inflammation. The extract had no analgesic effect in tail-flick test up to the highest dose used (6 g/kg). No abnormal behavior and lethality was observed by the extract up to 6 g/kg. Preliminary phytochemical analysis showed the presence of triterpenoids, saponins and simple phenols in the extract. [Copyright &y& Elsevier]

Ferula gummosa Boiss. (Apiaceae) which has been used as an antiepileptic remedy in Iranian traditional medicine was evaluated for anticonvulsant activity against experimental seizures. The seed acetone extract of F. gummosa protected mice against tonic convulsions induced by maximal electroshock (the median effective dose [ED50]=198.3 mg/kg) and especially by pentylenetetrazole (ED50=55 mg/kg). Neurotoxicity (sedation and motor impairment) of the extract was assessed by the rotarod test and the median toxic dose (TD50) value of 375.8 mg/kg was obtained. Preliminary phytochemical analysis showed the presence of terpenoids and alkaloids in the extract. The acceptable acute toxicity of the extract recommends further studies to determine the mechanism(s) and compound(s) involved in the anticonvulsant activity. [Copyright &y& Elsevier]

Abstract: The anticonvulsant activity of acetone extract of the seeds of Heracleum persicum (Umbelliferae) was examined against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures in mice. The extract showed a dose-dependent protective effect in both seizure models. However, the sedative dose of the extract, examined by rotarod test, was close to the anticonvulsant doses. Preliminary phytochemical analysis showed the presence of alkaloids, terpenoids, triterpenes and steroids in the extract. The observed pharmacological effects could be due to alkaloids, terpenoids and triterpenes present in the plant. [Copyright &y& Elsevier]

• DHEA is endogenous metabolite of fish ω-3 fatty acid DHA. • DHA and DHEA have similar chemical structure to the endogenous cannabinoids. • DHA and DHEA decreased seizure susceptibility of mice by activating CB1 receptors. • DHEA showed more potency than its parent lipid DHA. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most recognized omega-3 unsaturated fatty acids showing neuroprotective activity in animal and clinical studies. Docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) are non-oxygenated endogenous metabolites of DHA and EPA, which might be in charge of the anti-seizure activity of the parent molecules. We examined the effect of these metabolites on the threshold of clonic seizures induced by pentylenetetrazole (PTZ). DHEA and EPEA possess similar chemical structure to the endogenous cannabinoids. Therefore, involvement of cannabinoid (CB) receptors in the anti-seizure effect of these metabolites was also investigated. DHA, DHEA, EPEA, AM251 (CB1 receptor antagonist), and AM630 (CB2 receptor antagonist) were administered to mice by intracerebroventricular (i.c.v.) route. Threshold of clonic seizures was determined 10 and/or 15 min thereafter by intravenous infusion of PTZ. The effect of DHA and DHEA on seizure threshold was then determined in mice, which were pretreated with AM251 and/or AM630. DHA (300μM), and DHEA (100 and 300 μM) significantly increased seizure threshold, 15 (p < 0.05) and 10 min (p < 0.01) after administration, respectively. DHEA was more potent than its parent lipid, DHA in decreasing seizure susceptibility. EPEA (300 and 1000 μM) did not change seizure threshold. AM251 fully prevented the increasing effect of DHA and DHEA on seizure threshold (p < 0.05). AM630 did not inhibit the effect of DHA and DHEA on seizure threshold. This is the first report indicating that DHEA but not EPEA, possesses anti-seizure action via activating CB1 receptors. DHEA is more potent than its parent ω-3 fatty acid DHA in diminishing seizure susceptibility. [ABSTRACT FROM AUTHOR]

Rabies is a lethal infectious disease caused by rabies virus (RABV). Fear and anxiety are the distinguished symptoms in rabies patients. Fusion of RABV envelope glycoprotein (RVG) to host cell membrane initiates rabies pathogenesis via interacting with PDZ domain of signaling proteins. We assessed the anxiety-like behaviors, and hypothalamic–pituitary–adrenal axis (HPA) response to RVG infection. Contribution of PDZ binding motif (PBM) of RVG to the observed effects was also examined using a mutant form of RVG, ΔRVG, with deleted last four amino acids at PBM C-terminus. Lentiviral vectors containing RVG and/or ΔRVG genes were injected into the rat brain areas involved in anxiety including hypothalamus, dorsal hippocampus, and amygdala. RVG/ΔRVG neural expression was examined by fluorescent microscopy. Anxiety-like behaviors were assessed by elevated plus maze (EPM) and open field (OF) tasks. HPA response was evaluated via measuring corticosterone serum level by ELISA technique. RVG/ΔRVG were successfully expressed in neurons of the injected areas. RVG, but not ΔRVG, infection of hypothalamus and amygdala increased the time spent in EPM open arms, and OF total distance moved and velocity. RVG, but not ΔRVG, infection of hypothalamus and dorsal hippocampus increased corticosterone level. The anxiety-like behaviors and exploratory/locomotor activities of rats with RVG infection in hypothalamus, and amygdala are mediated by PBM of RVG. The HPA response to RVG infection of hypothalamus and dorsal hippocampus is dependent to PBM of RVG. Triggering anxiety-related signaling by PBM of RVG seems to be one of the mechanisms involved in anxiety behaviors seen in patients with rabies. [ABSTRACT FROM AUTHOR]

Abstract Introduction The vulnerability of hippocampal formation to ischemic insult has been documented in both humans and animal models. Ischemic injury induction through photothrombosis is an invasive and reproducible model of ischemic stroke which provides the ability to induce ischemia selectively in any desired area. In this study, we describe a method to induce selective unilateral hippocampal ischemia in rat through modified photothrombotic model. Methods Male wistar rats (n = 66) were subjected to stereotaxic surgery to insert a guide cannula just above the ascending part of hippocampal fissure. After recovery femoral vein was cannulated and rats were mounted in stereotaxic frame to optical fiber insertion in guide cannula and illumination of hippocampal fissure for 25 min. Rose Bengal dye was slowly injected through femoral vein during the first two-minute of illumination. Twenty-four hours later, infarct volume and histological change were evaluated in rat hippocampus. Cognitive function was also evaluated 48 h after ischemia induction. Results This procedure caused significant neuronal necrosis and infarct formation in the right hemisphere hippocampus. The infarct size was consisted in different subjects and was paralleled to cognitive impairment. The mean volume of infarction was 6.5% which affected whole right hippocampus and caused significant cognitive impairment compared to sham group (P < 0.001). Discussion The method described in this study provides the ability of selective hippocampal ischemia induction and study of hippocampal injury consequences following ischemia or other neurodegenerative disease that affect hippocampus. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), as an expanding public health epidemic, is a common cause of death among youth. TBI is associated with cognitive deficits and memory impairment. Hydrogen sulfide (H 2 S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. In the present study the potential neuroprotective role of sodium hydrosulfide (NaHS), an H 2 S donor on TBI induced memory deficit in a rat model of controlled cortical impact (CCI) injury was investigated. CCI model was used to induce TBI. Male rats were randomly assigned into the following groups: control, sham, sham treated with NaHS, TBI, and TBI treated with NaHS (3 and 5 mg/kg). NaHS was injected intraperitoneally 5 min before TBI induction. Learning and memory were assessed using Morris water maze (MWM) on days 8–12 following injury. CCI resulted in MWM deficits. Injured animals showed a slower rate of acquisition with respect to the sham-operated animals [F (1, 24) = 13.97, P < 0.01, two-way ANOVA]. NaHS improved spatial memory impairment of injured rats. Treatment with NaHS (5 mg/kg) decreased the escape latency [F (1, 24) = 7.559, P < 0.05, two-way ANOVA] and traveled distance [F (1, 12) = 6.398, P < 0.05, Two way ANOVA)]. In probe test, injured animals spent less time in target zone (P < 0.05, unpaired t -test) and NaHS did not have any effect on this parameter (p > 0.05, one way ANOVA). These findings suggest that NaHS has a neuroprotective effect on TBI-induced memory impairment in rats. [ABSTRACT FROM AUTHOR]