Atorvastatin Prevent the Neuron Loss in the Hippocampal Dentate Gyrus Region through its Anti-oxidant and Anti-apoptotic Activities

Background: Atorvastatin is a member of statins, which has shown positive vascular effects, anti-oxidant, antiplatelet, and anti-apoptotic properties. Objective: In this study, we hypothesized that atorvastatin could prevent the neurons lost in the hippocampal dentate gyrus region after transient global ischemia/reperfusion (I/R) through its anti-oxidant and anti-apoptotic activities. Method: Twenty-four male Wistar rats 12-13 weeks old and weighing 250–300 g, were divided randomly into four groups: control, I/R, vehicle (I/R treated with NaCl) and experiment (I/R treated with atorvastatin, 10 mg/kg) and rats were sacrificed 96 hours after I/R. Quantitative expression of genes (caspase 8, p53, bax, bcl2, cytochrome c) was studied. The MDA level, SOD, CAT, and GPx activities were measured with biochemical tests. To detect apoptotic cells, TUNEL and Nissl staining were performed. Mitochondria were prepared from the hippocampus rats, used to the quantification of mitochondrial ROS, ATP level, GSH content, membrane potential, cytochrome c release, and determination of mitochondrial swelling. Results: Atorvastatin attenuated the overexpression of bax, cytochrome C, p53, and caspase8 mRNAs and induced expression of bcl-2 mRNA (P<0.001). Atorvastatin treatment increased anti-oxidant enzyme levels (P<0.01). Treatment with atorvastatin reduced the number of TUNEL-positive cells. It could decrease the cytochrome c release (P<0.01), inhibit the decrease of MMP (P<0.001) and increased the ATP level (P<0.001) in mitochondrial hippocampal in compared with I/R group. Conclusion: Atorvastatin treatment in I/R rats decreases oxidative stress, production of ROS, apoptosis rate in neuronal cells, and improves the mitochondrial function. Hence, atorvastatin have a proper neuronal protective effect against the I/R injury in the brain.

Testosterone and Adult Neurogenesis

It is now well established that neurogenesis occurs throughout adulthood in select brain regions, but the functional significance of adult neurogenesis remains unclear. There is considerable evidence that steroid hormones modulate various stages of adult neurogenesis, and this review provides a focused summary of the effects of testosterone on adult neurogenesis. Initial evidence came from field studies with birds and wild rodent populations. Subsequent experiments with laboratory rodents have tested the effects of testosterone and its steroid metabolites upon adult neurogenesis, as well as the functional consequences of induced changes in neurogenesis. These experiments have provided clear evidence that testosterone increases adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation. Whether this is a result of androgens acting directly on receptors of new neurons remains unclear, and indirect routes involving brain-derived neurotrophic factor (BDNF) and glucocorticoids may be involved. In vitro experiments suggest that testosterone has broad-ranging neuroprotective effects, which will be briefly reviewed. A better understanding of the effects of testosterone upon adult neurogenesis could shed light on neurological diseases that show sex differences.

Optogenetic silencing of immature and mature neurons in dentate gyrus to assess their roles in memory discriminations

ABSTRACTDiscriminating similar memories and events depends on the dentate gyrus region of the hippocampus. This region is also distinctive because neurogenesis continues in adulthood. Whether both mature and immature granule cells play a role in memory discrimination, and whether the roles are distinct is actively investigated. Here we demonstrate that manipulating either mature or immature granule cells can impair discrimination of similar active place avoidance memories, but the manipulations have different effects. We also observe that prior experience modulates which memories are compromised by inactivation of immature neurons. These data demonstrate the importance of the dentate gyrus network of cells for memory discrimination.

Effects of L-655,708 on expression changes of GABA, glutamate, and beta-endorphin induced by propofol anesthesia in rats

Anesthetics are considered to be one of the important inducing factors of postoperative cognitive dysfunction (POCD). The hippocampal region of the rat is one of the action sites of general anesthesia drugs. L 655,708, a reverse agonist of gamma aminobutyric acid (GABA) receptor, can significantly improve short-term memory dysfunction in mice after anesthetized with isoflurane. So the purpose of this study is to investigate the effects of L-655,708 on expression of GABA, glutamate (GLU), and beta-endorphin (β-EP) in the dentate gyrus region of the hippocampus and cognition of rats anesthetized with propofol. In all, 30 male Sprague–Dawley (SD) rats were randomly allocated into the control group, sham group, and L-655,708 group, with 10 in each group. The cognitive function of rats was measured by Morris water maze before and 1 h after administration. Then the rats were sacrificed for brain tissues. Immunohistochemistry was used to study the expression of GABA, GLU, and β-EP in the hippocampus of anesthetized rats in each group. Compared with the control group, the latency of the sham group and L-655,708 group were significantly prolonged after administration ( P < 0.05). However, L-655,708 could shorten the prolonged latency ( P < 0.05). There was no significant difference in times of accessing original platform area between the three groups before and after medication ( P > 0.05). The expression level of GABA in the dentate gyrus region of hippocampus of rats in the sham group was significantly higher than that in the control group ( P < 0.05), while the expression level in the L-655,708 group was significantly lower than that in the sham group ( P < 0.05). No significant difference was found in the expression of GLU in the dentate gyrus region of hippocampus of rats in each group ( P > 0.05). Compared with the control group, the expression of β-EP was significantly lower in the dentate gyrus region of the hippocampus of sham group rats ( P < 0.05). However, the expression of β-EP in the L-655,708 group was significantly higher than that in the sham group ( P < 0.05). Cognitive dysfunction in rats anesthetized with propofol may be related to high expression of GABA and low expression of β-EP in the hippocampus. The mechanism of L-655,708 in reducing the cognitive impairment in propofol anesthetized rats may be bound up with down-regulating the expression of GABA and increasing the expression of β-EP in the hippocampus.