Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • The acetylcholinesterase AChE inhibitor tacrine THA exerts n

    2024-02-09

    The acetylcholinesterase (AChE) inhibitor, tacrine (THA), exerts neuroprotective effects in time- and does-dependent manners against glutamate neurotoxicity (Takada-Takatori et al., 2006a, 2006b) and amyloid-β protein toxicity in PC12, a pheochromocytoma line (Wang et al., 2002; Xiao et al., 2000). We previously reported that cognitive deficits in db/db mice, an animal model of type 2 diabetes, were accompanied by decreases in the number of medial septal cholinergic neurons and the expression levels of VEGF in the hippocampus and that the administration of THA reversed these behavioral and pathological alterations. These findings suggested that the VEGF/VEGFR2 loop is involved in the amelioration of cognitive and emotional deficits (Zhao et al., 2012). Moreover, in in vitro studies using organotypic hippocampal slice cultures, we found that a treatment with THA rescued hippocampal neurons from excitotoxicity-induced long-lasting hippocampal cell damage via not only the endogenous Tanshinone IIA---sulfonic sodium (ACh) stimulation of a muscarinic M1 receptor subtype (Inada et al., 2013, 2014), but also via paracrine VEGF signaling between astrocytes and hippocampal neurons or autocrine VEGF signaling in hippocampal neurons (Inada et al., 2014). Our findings suggested a link between cholinergic systems and VEGF signaling systems in the brain. In the present study, we investigated the cholinergic mechanisms regulating VEGF expression and VEGF signaling in primary cultured cortical neurons and astrocytes. We also elucidated these mechanisms in the medial septum of the mouse brain for the following reasons. The medial septum is a major nucleus in which cholinergic neurons are located and project their nerve terminals to the hippocampus, thereby playing an important role in learning and memory (Chen et al., 2017; Jeong et al., 2014; Khakpai et al., 2013). Furthermore, the degeneration of septal cholinergic neurons and cognitive deficits in olfactory bulbectomized (OBX) animals, a model of dementia including AD, were found to be attenuated by the administration of THA (Le et al., 2013).
    Materials and methods
    Results
    Discussion The present study demonstrated that endogenous ACh exerts up-regulatory effects on the expression of VEGF in neurons and astrocytes via different cholinergic pathways: nicotinic AChR in neurons and muscarinic AChR in astrocytes, and thereby activates VEGF-VEGFR2 signaling in medial septal cholinergic neurons via autocrine secretion from cholinergic neurons and/or paracrine secretion from astrocytes. These results support the hypothesis presented in previous studies that endogenous ACh plays a rescuing role for neuronal cell damage via autocrine VEGF signaling in neurons or paracrine VEGF signaling between astrocytes and neurons (Inada et al., 2013, 2014). This mechanism may also be implicated in the ameliorative effects of THA in various animal models of dementia including diabetic animals (Zhao et al., 2012). In the present study, we found that the THA treatment significantly increased VEGF mRNA expression levels in primary cultured neurons, and that these effects were accompanied by a slight increase in neuronal VEGF secretion. However, THA treatment had no effect on the intracellular VEGF level of neurons. Moreover, VEGF mRNA expression, VEGF secretion and intercellular VEGF expression in astrocytes were also significantly increased by CCh. These results suggest that the activation of cholinergic signaling systems by endogenous ACh facilitates the biosynthesis and secretion of VEGF by neurons and astrocytes. The reason why THA treatment failed to affect VEGF secretion and intracellular VEGF expression is unclear. However, a couple of reasons for this failure are considered. First, secretion of endogenous VEGF and intracellular VEGF expression may be fully up-regulated by endogenous ACh released from neurons. Second, VEGF was taken in neurons and translocated to nucleus (Domingues et al., 2011; Lin et al., 2017). As the former basis, we revealed that THA increased the endogenous ACh from neurons, and even THA-untreated neurons also increased endogenous ACh in a time-dependent manner. In contrast to neuronal responses to THA, VEGF mRNA expression levels in astrocytes were not altered by the THA treatment. The lack of a response by astrocytes to THA may be due to a difference in the activity of AChE in the cultured medium between primary cultured neurons and astrocytes. A previous study reported that neuronal and non-neuronal cells show the differential localization of AChE and that astrocytes exhibit weaker AChE activity than neuronal cells (Thullbery et al., 2005). Thus, even if the culture medium of astrocytes contains AChE, the inhibition of its activity by THA may be insufficient to stimulate the cholinergic receptors involved in the up-regulation of VEGF mRNA expression in astrocytes. The difference of AChE activity may be due to the difference of culture medium between neuron and astrocyte. Sünwoldt et al. reported that the composition of culture medium influenced the metabolism and cell function of neurons and astrocytes (Sünwoldt et al., 2017).