Abstract
Xanomeline, a muscarinic acetylcholine receptor agonist, is one of the first compounds that was found to be effective in the treatment of schizophrenics and attenuating behavioral disturbances of patients with Alzheimer’s disease (AD). However, its role in ischemia-induced injury due to oxygen and glucose deprivation (OGD) remains unclear. Primary rat neuronal cells were exposed to OGD and treated with xanomeline. The effects of xanomeline on apoptosis, cell viability, lactate dehydrogenase (LDH) levels, and reactive oxygen species (ROS) were determined using an Annexin V Apoptosis Detection Kit, a non-radioactive cell counting kit-8 (CCK-8) assay, colorimetric LDH cytotoxicity assay kit, and a dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay, respectively, and the expressions of Sirtuin 1, haem oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl-2), poly ADP-ribose polymerase (PARP), and hypoxia-inducible factor α (HIF-1α) as well as the level of phosphorylated kinase B (p-Akt) were determined by Western blotting. Compared with the control, xanomeline pretreatment increased the viability of isolated cortical neurons and decreased the LDH release induced by OGD. Compared with OGD-treated cells, xanomeline inhibited apoptosis, reduced ROS production, attenuated the OGD-induced HIF-1α increase and partially reversed the reduction of HO-1, Sirtuin-1, Bcl-2, PARP, and p-Akt induced by OGD. In conclusion, xanomeline treatment protects cortical neuronal cells possibly through the inhibition of apoptosis after OGD.
Highlights
Ischemic stroke is the second most common cause of death in China and it is the main cause of disability in the modern world (Chalela et al, 2004; Stonesifer et al, 2017)
A cell counting kit-8 (CCK-8) cell viability assay showed that 12 h oxygen and glucose deprivation (OGD) produced damage to the cortical neurons, which could be mitigated by xanomeline treatment (P < 0.01; Figure 1B)
lactate dehydrogenase (LDH) release was significantly increased in the OGD group when compared to the control; xanomeline significantly inhibited LDH release in OGD-exposed cortical neurons (P < 0.01; Figure 1C)
Summary
Ischemic stroke is the second most common cause of death in China and it is the main cause of disability in the modern world (Chalela et al, 2004; Stonesifer et al, 2017). Xanomeline is an agonist of the orthosteric muscarinic acetylcholine receptor, which is often referred to as M1/M4 preferring, and of the 5-HT1A receptor in the cerebral cortex and hippocampus (Mirza et al, 2003). Xanomeline improves positive and negative syndromes, as well as cognitive symptoms in patients with schizophrenia (Jones et al, 2015). Xanomeline treatment produced robust improvements in verbal learning and short-term memory in a cognitive test battery (Shekhar et al, 2008). Xanomeline increases soluble amyloid precursor protein (APP) release from Chinese hamster ovary-m1 cells (Eckols et al, 1995). Xanomeline had agonistic activity at the M1 muscarinic acetylcholine receptor in all brain regions (Odagaki et al, 2016). We conclude that xanomeline may have a direct impact on brain function
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