α7 Nicotinic Acetylcholine Receptor May Be a Pharmacological Target for Perioperative Neurocognitive Disorders

Abstract

Background: The α7 nicotinic acetylcholine receptor (α7nAChR) is a promising therapeutic target in neurodegenerative diseases. This study examined the effects of surgery and anesthesia on α7nAChR expression in the central nervous system and determined the mechanisms by which α7nAChR mediates neuroprotection in perioperative neurocognitive disorders (PNDs) in aged mice.Methods: Eighteen-month-old male C57BL/6J mice underwent aseptic laparotomy under isoflurane anesthesia, maintaining spontaneous ventilation to establish the PNDs model. Agonists and antagonists of the α7nAChR and tropomyosin receptor kinase B (TrkB) receptors were administered before anesthesia. The α7nAChR expression, peripheral as well as hippocampal interleukin-1β (IL-1β), and the brain-derived neurotrophic factor (BDNF) levels were assessed. Separate cohorts of aged mice were tested for cognitive decline using the Morris water maze (MWM).Results: Surgery and anesthesia significantly suppressed α7nAChR expression in the hippocampus and cortex. Surgery-induced IL-1β upregulation in the serum as well as hippocampus and hippocampal microglial activation were reversed by the α7nAChR agonist. A significant reduction in the hippocampal BDNF levels were also observed. The α7nAChR stimulation reversed, and α7nAChR suppression promoted BDNF reduction in the hippocampus. Blocking the BDNF/TrkB signaling pathway abolished α7nAChR-induced neuroprotection in PNDs, as evidenced by poor cognitive performance in the MWM test.Conclusions: These data reveal that α7nAChR plays a key role in PNDs. The mechanisms of the anti-inflammatory pathway and BDNF/TrkB signaling pathways are involved in α7nAChR-meidiated neuroprotection in PNDs.

Increased brain cytokine level associated impairment of vigilance and memory in aged rats can be alleviated by alpha7 nicotinic acetylcholine receptor agonist treatment

“…Mice with cognitive impairment due to intracerebroventricular streptozotocin injection were not only improved in memory tests by alpha7 nAChR agonist GTS-21 but the drug also blocked the streptozotocin-induced overproduction of TNFalpha, IL-1beta, and IL-6 in the hippocampus and the cortex [ 51 ]. Alpha7 nAChR agonists also decrease IL-1beta levels and increase BDNF levels in mice with perioperative neurocognitive disorder [ 52 ]. Positive allosteric modulators (PAM) of the alpha7 nAChR also effectively reduce neuroinflammation.…”

α7 nicotinic acetylcholine receptor in memory processing

“…Considering that neuroinflammation was postulated as a pathological mechanism in AD (Kinney et al, 2018), several studies attempt to point out that α7 nAChRs may be a key element in AD pathophysiology (Hoskin et al, 2019). Moreover, α7 nAChRs influence the expression of glutamate receptors and neurotrophic factors, making them a key element for targeting cognitive decline in AD (Cai et al, 2022; Medeiros et al, 2014; Roberts et al, 2021; Wei et al, 2022).…”

“…Moreover, Ras GTPase inhibitor enhanced hippocampal brain‐derived neurotrophic factor (BDNF) concentration, which was reversed by the antagonism of α7 nAChRs (Cai et al, 2022). In line with this research, a mice model of perioperative cognitive disorder was used for assessing the effects of α7 nAChR modulation on a hippocampal‐dependent spatial learning task (Wei et al, 2022). Following an aseptic laparotomy, these authors found a decrease of BDNF protein expression in the hippocampus, which was reversed by α7 nAChR activation and promoted by their inhibition.…”

Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice

“…In second experiment, K252a (an antagonist of the TrkB receptor, MCE, 99533-80-9) diluted in 0.1% methyl sulfoxide (DMSO) was intraperitoneally administered at 25 μg/kg per injection daily for 15 days before hUC-MSC transplantation. Based on previous reports, a low concentration of K252a was selected to avoid any unwanted effects [25][26][27]. The same amount of DMSO and normal saline were administered intraperitoneally to mice in other groups.…”

“…An escape platform (diameter, 100 mm) was placed in the first quadrant and submerged 15 mm below the water surface. The MWM test consists of 5 days of spatial acquisition trials, and a 1-day probe trial was performed as previously described [26,28]. In the spatial acquisition trials, mice were trained to find the hidden platform within 60 s using distinctive distal visual cues around the apparatus over four consecutive trials conducted once per day.…”