Huzhang glycoside inhibits fentanyl induced apoptosis of hippocampal neurons by activating TrkA
Although general anesthesia is considered a safe and routine medical procedure used by millions of clinics around the world every day, research in recent decades has found that in some cases, general anesthesia may cause severe and irreversible neurological damage to the central nervous system, especially in young and infant patients. Among several widely used anesthetics, fentanyl has been shown to induce neuronal growth cone collapse, neural mutagenicity, and other histopathological damage in animal models. Recent studies have shown that drug or genetic interventions can have a salvage effect on fentanyl induced neurotoxicity, for example, dexamethasone can alleviate fentanyl induced nerve damage through the PI3K/Akt and ERK signaling pathways.

Brain derived neurotrophic factor (BDNF) is a biologically active protein encoded by the BDNF gene, belonging to the neurotrophic factor family. It is concentrated in the nervous system and exerts biological effects by binding to its high affinity primary receptor tyrosine kinase receptor (Trk) to regulate downstream signal transduction pathways. BDNF plays an important role in the growth, maturation, differentiation, and survival of neurons and synapses in the central nervous system, and maintains mature neurons by inhibiting neuronal apoptosis, improving the pathological state of neurons, and exerting long-term enhancement effects, thereby promoting understanding and memory ability. In addition, BDNF/Trk can also regulate dopamine release, induce dopamine related behavior, improve or worsen cognition and memory by interacting with the dopaminergic system in the midbrain limbic lobe. Function. Animal experiments have shown that knockout of the tyrosine kinase receptor gene in mice significantly impairs long-term potentiation, comprehension, and memory abilities. Polygonatum sibiricum glycoside is a natural active ingredient extracted from the dried rhizomes of traditional Chinese medicine Polygonum cuspidatum. Recent studies have shown that Polygonatum sibiricum glycoside can prevent neurodegenerative diseases, including Parkinson’s disease or Alzheimer’s disease, by increasing free radical scavenging or inducing starch beta protein degradation. However, it is currently unclear whether Polygonatum sibiricum glycoside plays a neuroregulatory role in anesthesia induced central nervous system toxicity. Therefore, we pre treated hippocampal neurons with Polygonatum sibiricum glycoside to detect its neuroprotective function and potential mechanism after fentanyl anesthesia.

 

The sustained state of anesthesia caused by high concentrations of general anesthetics (such as fentanyl) may cause ischemic hypoxia and edema, and induce the release of excitatory amino acids, the influx of sodium and calcium, and the activation of the Caspase protein family. The increased expression of Caspase further activates downstream effectors, leading to apoptosis of nerve cells, including hippocampal neurons, and inducing various pathological changes, such as neuronal loss and glial cell proliferation, resulting in acute and sustained damage to the central nervous system, especially damage to neurons in the hippocampus and other peripheral systems. Although rare, it may cause serious and permanent damage to the developing brain of young and infant patients. Therefore, studying the potential mechanisms of anesthesia induced central nervous system toxicity and its effective preventive drugs has important clinical significance. The sentence is:, Our research found that fentanyl treatment can significantly induce neuronal cell apoptosis, inhibit TrkA phosphorylation activation, promote Caspase-9 expression, and impair learning and cognitive abilities in mice. Meanwhile, puerarin pretreatment can reverse fentanyl induced neuronal apoptosis and cognitive impairment in mice.

Polygonum cuspidatum is a perennial shrub like herbaceous plant in the Polygonaceae family. It is used as medicine with dried rhizomes and roots. Polygonum cuspidatum mainly contains anthraquinones, flavonoids, and phenolic compounds, which have various pharmacological effects, including anti-inflammatory, antiviral, antibacterial, lipid-lowering, antithrombotic, cardioprotective, antioxidant, anti-tumor, and neuroprotective effects. Polygonatum sibiricum glycoside is an active ingredient extracted from its dried rhizome. Studies have shown that Polygonatum sibiricum glycoside has good neuroprotective effects. It can downregulate NF kB (nuclear factor kB) activity by upregulating the expression of GLI-1 (glioma associated oncogene protein 1) and SOD1 (superoxide dismutase), improve the blood-brain barrier, and protect the brain from damage caused by middle cerebral artery ischemia, alleviate learning and memory disorders, and improve cognitive impairment; In an in vivo animal model of spinal cord injury, puerarin can exert neuroprotective effects by increasing superoxide dismutase, reducing malondialdehyde, and inhibiting apoptosis related signaling pathways. Recent studies have found that treatment with sphingosine after cerebral ischemia can promote apoptosis of hippocampal neurons by activating Caspase-9/Caspase-3, leading to decreased learning and memory abilities and impaired learning and memory abilities. Meanwhile, puerarin can protect cortical neurons from ischemic damage through the neurotrophic signaling pathway and inhibit the activation of Caspase-3 (cysteine aspartic protease -3) by downregulating Caspase-9, thereby exerting neuroprotective functions and improving the learning and memory abilities of mice. Our research results show that puerarin can significantly inhibit fentanyl induced upregulation of Caspase-9 in neuronal cell apoptosis, exert neuroprotective effects, and improve learning and memory abilities in mice.

The tropomyosin receptor kinase (Trk) receptors (including TrkA, TrkB, and TrkC) are dynamically expressed during the development of hippocampal neurons. They are phosphorylated by binding to brain-derived neurotrophic factor, initiating related signaling pathways and interacting with neurotrophin signaling pathways to regulate the maturation, differentiation, survival, synaptic remodeling, or damage of hippocampal neurons. Studies have shown that activating TrkA/B in the neurotrophin signaling pathway can reduce anesthesia induced neurotoxicity. Our study found that puerarin can significantly inhibit fentanyl induced neuronal apoptosis and exert neuroprotective effects by upregulating phosphorylated TrkA.

In summary, our results indicate that puerarin can reduce fentanyl induced hippocampal neuronal apoptosis by inhibiting the upregulation of Caspase-9, promoting TrkA phosphorylation activation, exerting neuroprotective effects, and improving learning and memory abilities in mice.