Corrigendum to: Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells.

[This corrects the article on p. 679 in vol. 22, PMID: 30402028.].

Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.

Preventing Donepezil-Induced Adverse Effects Through N-acetylcysteine Co-Administration.

Background: Drug-induced adverse symptoms affect patients' quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer's disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Objective: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and investigate the underlying mechanisms. Methods: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. Results: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+]i levels in muscle cells. Conclusions: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients.

Anti­inflammatory role of Prunus persica L. Batsch methanol extract on lipopolysaccharide­stimulated glial cells.

Glial cells are the resident immune cells of the central nervous system. Reactive glial cells release inflammatory mediators that induce neurotoxicity or aggravate neurodegeneration. Regulation of glial activation is crucial for the initiation and progression of neuropathological conditions. Constituents of the peach tree (Prunus persica L. Batsch), which has a global distribution, have been found to exert therapeutic effects in pathological conditions, such as rashes, eczema and allergies. However, the therapeutic potential of its aerial parts (leaves, fruits and twigs) remains to be elucidated. The present study aimed to evaluate the anti­inflammatory role of P. persica methanol extract (PPB) on lipopolysaccharide (LPS)­stimulated glial cells. High­performance liquid chromatography coupled with tandem mass spectrometry analysis showed that PPB contained chlorogenic acid and catechin, which have antioxidant properties. Western blot and reverse transcription polymerase chain reaction results indicated that PPB reduced the transcription of various proinflammatory enzymes (nitric oxide synthase and cyclooxygenase­2) and cytokines [tumor necrosis factor­α, interleukin (IL)­1ß and IL­6] in LPS­stimulated BV2 cells. In addition, PPB inhibited the activation of NF­κB and various mitogen­activated protein kinases required for proinflammatory mediator transcription. Finally, nitrite measurement and immunocytochemistry results indicated that PPB also suppressed nitrite production and NF­κB translocation in LPS­stimulated primary astrocytes. Thus, PPB may be used as a potential therapeutic agent for neurodegenerative diseases and neurotoxicity via the suppression of glial cell activation.

Various approaches for measurement of synaptic vesicle endocytosis at the central nerve terminal.

At the presynaptic terminal, neurotransmitters are stored in synaptic vesicles (SVs), which are released and recycled via exo- and endocytosis. SV endocytosis is crucial for sustaining synaptic transmission by maintaining the SV pool. Many studies have shown that presynaptic dysfunction, particularly impairment of SV endocytosis, is related to neurological disorders. Notably, the presynaptic terminal is considered to be a sensitive structure because certain presynaptic dysfunctions, manifested as impaired SV endocytosis or ultrastructural changes in the presynaptic terminal, can be observed before there is a biochemical or pathological evidence of a neurological disorder. Therefore, monitoring and assessing the presynaptic function by SV endocytosis facilitates the development of early markers for neurological disorders. In this study, we reviewed the current methods for assessing and visualizing SV endocytosis at the central nerve terminal.

Comprehensive behavioral analyses of anoctamin1/TMEM16A-conditional knockout mice.

AIMS: Anoctamin-1 (TMEM16A) is a calcium-activated chloride channel that is involved in numerous physiological conditions. Its role has been identified in electrophysiological and histological studies of genetic knockout animals. Recent cellular localization studies have shown that anoctamin-1 is co-expressed with presynaptic proteins, therefore its role in presynaptic terminals has been suggested. However, behavioral studies are lacking because conventional knockouts of anoctamin-1 are lethal after birth. In this study, we explored the role of anoctamin-1 in presynaptic terminals by analyzing the behavior of mice with conditional knockouts of anoctamin-1 in synapsin1-expressing cells. MAIN METHODS: Using a synapsin1-Cre system, we selectively ablated anoctamin-1 in synapsin1 expressing cells. The mice were used in the behavioral experiments when they were between 6 and 9 months of age. KEY FINDINGS: The mice with the conditional knockout of anoctamin-1 in synapsin1-expressing cells displayed impaired social behavior. In addition, the mice showed depressive-like behavior and decreased weight. However, these animals displayed normal locomotor activity, cognitive function, and motor coordination. SIGNIFICANCE: These results suggested that anoctamin-1 is involved in psychiatric behavior because of its role in the regulation of synaptic transmission in presynaptic terminals.