[Show abstract][Hide abstract] ABSTRACT: The present study investigated whether cannabidiol (CBD), a major non-psychoactive constituent of marijuana, protects against hippocampal neurodegeneration and cognitive deficits induced by brain ischemia in adult mice. Male Swiss mice were subjected to a 17 min of bilateral common carotid artery occlusion (BCCAO) and tested in the Morris water maze 7 days later. CBD (3, 10, and 30 mg/kg) was administered 30 min before and 3, 24, and 48 h after BCCAO. After behavioral testing, the brains were removed and processed to evaluate hippocampal cell survival and degeneration using Nissl staining and FluoroJade C histochemistry, respectively. Astroglial response was examined using immunohistochemistry for glial fibrillary acidic protein (GFAP). CBD (3-30 mg/kg) improved spatial learning performance in BCCAO mice. The Nissl and FJC staining results showed a decrease in hippocampal neurodegeneration after CBD (10 and 30 mg/kg) treatment. GFAP immunoreactivity was also decreased in ischemic mice treated with CBD (30 mg/kg). These findings suggest a protective effect of CBD on neuronal death induced by ischemia and indicate that CBD might exert beneficial therapeutic effects in brain ischemia. The mechanisms that underlie the neuroprotective effects of CBD in BCCAO mice might involve the inhibition of reactive astrogliosis.
Neurotoxicity Research 02/2014; 26(4). DOI:10.1007/s12640-014-9457-0 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study examined the behavioral and neurohistological changes induced by the bilateral common carotid artery occlusion (BCCAO) model of brain ischemia in Swiss mice. The post-ischemic behavioral effects of 17min BCCAO were recorded 7, 14, and 28 days after reperfusion in the Morris water maze, open field, and elevated plus maze to assess spatial learning and memory, general locomotor activity, and levels of anxiety-like behavior, respectively. After behavioral testing, the brains were removed and processed to evaluate hippocampal neurodegeneration using Nissl staining and Fluoro-Jade C histochemistry and hippocampal neurogenesis using doublecortin immunohistochemistry. BCCAO induced memory impairment 7 and 14 days after reperfusion, with apparent functional recovery 28 days later. Anxiety-related behaviors remained elevated in ischemic compared to sham mice tested 28 days after reperfusion. Hippocampal neurodegeneration was detected in all hippocampal subfields (CA1-CA4) from day 7 to day 28. Decreased hippocampal neurogenesis was observed 14 and 28 days after BCCAO. The effects of BCCAO on spatial memory were transient, whereas anxiety-like behavior was persistent and might be related to CA3 hippocampal injury induced by BCCAO in mice.
Behavioural brain research 04/2013; 249. DOI:10.1016/j.bbr.2013.04.010 · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transient global brain ischemia causes delayed neuronal death in the hippocampus that has been associated with impairments in hippocampus-dependent brain function, such as mood, learning, and memory. We investigated the expression of voltage-dependent Kcnh1 and Kcnh5, ether à go-go-related Eag1 and Eag2 (K(V) 10.1 and K(V) 10.2), and small-conductance calcium-activated SK3 (K(Ca) 2.3, Kcnn3) K(+) channels in the hippocampus in rats after transient global brain ischemia. We tested whether the expression of these channels is associated with behavioral changes by evaluating the animals in the elevated plus maze and step-down inhibitory avoidance task. Seven or tweny-eight days after transient global brain ischemia, one group of rats had the hippocampus bilaterally dissected, and mRNA levels were determined. Seven days after transient global brain ischemia, the rats exhibited a decrease in anxiety-like behavior and memory impairments. An increase in anxiety levels was detected 28 days after ischemia. Eag2 mRNA downregulation was observed in the hippocampus 7 days after transient global brain ischemia, whereas Eag1 and SK3 mRNA expression remained unaltered. This is the first experimental evidence that transient global brain ischemia temporarily alters Eag2. The number of intact-appearing pyramidal neurons was substantially decreased in CA1 and statistically measurable in CA2, CA3, and CA4 hippocampal subfields compared with sham control animals 7 or 28 days after ischemia. mRNA expression in the rat hippocampus. The present results provide further information for the characterization of the physiological role of Eag2 channels in the central nervous system.
Journal of Neuroscience Research 03/2012; 90(3):632-40. DOI:10.1002/jnr.22772 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study evaluated the effects of sildenafil using the 4-vessel occlusion (VO)/internal carotid artery (ICA) model of chronic cerebral hypoperfusion (HCC). We previously found that permanent, three-stage occlusion of the vertebral arteries (VA) and ICA, four-VO/ICA, with an interstage interval (ISI) of 7 days was innocuous and caused no structural or functional outcomes in rats. Therefore, before testing sildenafil, we evaluated how a reduction in the number of occlusion stages (from three stages to two) and a shortening of the ISI might impact the survival rate, capacity for learning and memory, and histomorphological integrity of the hippocampus. Survival decreased from 100% to 70%, 62%, and 0% as the ISI was shortened from 7 to 5, 4, or 3 days, respectively. Using the two shortest ISIs, sildenafil (0.75-3.0 mg/kg, p.o.) abolished the mortality rate by approximately 95%. Profound neurodegeneration occurred in the CA1, CA2, CA3, and CA4 hippocampal subfields after an ISI of 4 days. Despite this, however, memory performance was unaffected. Subsequently, sildenafil treatment reduced 4-VO/ICA-induced hippocampal damage. The present results suggest that sildenafil may be potentially beneficial in the treatment of chronic cerebral hypoperfusion. Further studies should examine the manner by which the chronic 4-VO/ICA model may effectively cause cognitive impairment, thus improving its applicability in testing the effects of drugs against structural and/or functional outcomes of chronic cerebral hypoperfusion.
Brain research bulletin 04/2010; 81(6):631-40. DOI:10.1016/j.brainresbull.2009.12.012 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was aimed to determine whether imipramine chronic treatment promotes neurogenesis in the dentate gyrus (DG) and interferes with neuronal death in the CA1 subfield of the hippocampus after transient global cerebral ischemia (TGCI) in rats. After TGCI, animals were treated with imipramine (20mg/kg, i.p.) or saline during 14 days. 5-Bromo-2'-deoxyuridine-5'-monophosphate (BrdU) was injected 24h after the last imipramine or saline injection to label proliferating cells. In order to confirm the effect of TGCI on neuronal death and cell proliferation, a group of animals was sacrificed 7 days after TGCI. Neurogenesis and neurodegeneration were evaluated by doublecortin (DCX)-immunohistochemistry and Fluoro-Jade C (FJC)-staining, respectively. The rate of cell proliferation increases 7 days but returns to basal levels 14 days after TGCI. There was a significant increase in the number of FJC-positive neurons in the CA1 of animals 7 and 14 days after TGCI. Chronic imipramine treatment increased cell proliferation in the SGZ of DG and reduced the neurodegeneration in the CA1 of the hippocampus 14 days after TGCI. Immunohistochemistry for DCX detected an increased number of newly generated neurons in the hippocampal DG 14 days after TGCI, which was not affected by imipramine treatment. Further studies are needed to evaluate whether imipramine treatment for longer time would be able to promote survival of newly generated neurons as well as to improve functional recovery after TGCI.