Neuroscience
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Antipsychotic drugs, including both typical such as haloperidol and atypical such as clozapine, remain the current standard for schizophrenia treatment. These agents are relatively effective in treating hallucinations and delusions. However, cognitive deficits are at present essentially either persistent or exacerbated following chronic antipsychotic drug exposure. ⋯ Chronic treatment with the class I and class II HDAC inhibitor SAHA prevented via HDAC2 the disruptive effects of MK801 on recognition memory. Additionally, chronic SAHA treatment affected transcription of numerous plasticity-related genes in the frontal cortex of control mice, an effect that was not observed in HDAC2-cKO animals. Together, these findings suggest that HDAC2 may represent a novel target to improve synaptic plasticity and cognition in treated schizophrenia patients.
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Painful neuropathic injuries are accompanied by robust inflammatory and oxidative stress responses that contribute to the development and maintenance of pain. After neural trauma the inflammatory enzyme cyclooxygenase-2 (COX-2) increases concurrent with pain onset. Although pre-treatment with the COX-2 inhibitor, meloxicam, before a painful nerve root compression prevents the development of pain, the pathophysiological mechanisms are unknown. ⋯ Oxidative damage following nerve root compression was found predominantly in neurons rather than glial cells. The expression of 8-OHG in DRG neurons at day 7 was reduced with meloxicam. These findings suggest that meloxicam may prevent the onset of pain following nerve root compression by suppressing inflammation and oxidative stress both centrally in the spinal cord and peripherally in the DRG.
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Peripheral immune activation could cause neuroinflammation, leading to a series of central nervous system (CNS) disorders, such as spatial learning and memory dysfunction. However, its pathogenic mechanism and therapeutic strategies are not yet determined. The present study aimed to investigate the therapeutic effects of sulforaphane (SFN) on lipopolysaccharide (LPS)-induced spatial learning and memory dysfunction, and tried to elucidate its relationship with the role of hippocampal brain-derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling pathway. ⋯ In addition, hippocampal levels of inflammatory cytokines, synaptic proteins, BDNF-tropomyosin receptor kinase B (TrkB) and mTOR signaling pathways were altered in the processes of LPS-induced cognitive dysfunction and SFN's therapeutic effects. Furthermore, we found that ANA-12 (a TrkB inhibitor) or rapamycin (a mTOR inhibitor) could block the beneficial effects of SFN on LPS-induced cognitive dysfunction, and that hippocampal levels of synaptic proteins, BDNF-TrkB and mTOR signaling pathways were also notably changed. In conclusion, the results of the present study suggest that SFN could elicit improving effects on LPS-induced spatial learning and memory dysfunction, which is likely related to the regulation of hippocampal BDNF-mTOR signaling pathway.
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Exposure to environmental enrichment (EE) has been a useful model for studying the effects of experience on brain plasticity, but to date, few is known about the impact of this condition on the brain functional networks that probably underlies the multiple behavioral improvements. Hence, we assessed the effect of an EE protocol in adult Wistar rats on the performance in several behavioral tasks testing different domains (Open field (OP): locomotor activity; Elevated-zero maze (EZM): anxiety-related behaviors; 5-choice serial reaction time task (5-CSRTT): attentional processes; 4-arm radial water maze (4-RAWM): spatial memory) in order to check its effectiveness in a wide range of functions. After this, we analyzed the functional brain connectivity underlying each experimental condition through cytochrome C oxidase (COx) histochemistry. ⋯ On the other hand, enriched rats showed more accuracy in the 4-RAWM, whereas 5-CSRTT performance was not significantly ameliorated by EE condition. In relation to COx functional connectivity, we found that EE reduced the number of strong positive correlations both in basal and training conditions, suggesting a modulating effect on specific brain connections. Our results suggest that EE seems to have a selective effect on specific brain regions, such as prefrontal cortex and hippocampus, leading to a more efficient brain connectivity.
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The brain is capable of improving from a chronically stressed state. The hippocampus in particular appears to "recover" from chronic stress-induced morphological and functional deficits following a post-stress rest period of several weeks. We previously found that hippocampal brain-derived neurotrophic factor (BDNF) was necessary for spatial ability to improve following a post-stress rest period. ⋯ In the second study, we tested whether the TrkB receptor was involved by administering daily systemic injections of ANA-12, a TrkB receptor antagonist, during the three-week post-stress rest period. ANA-12 prevented the improvement in spatial ability and CA3 apical dendritic complexity following the post-stress rest period. These data demonstrate that hippocampal BDNF acting via its TrkB receptor is necessary during the post-stress rest period in order to improve the impaired hippocampal structural and cognitive outcomes that occur in response to chronic stress.