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[Literature Review] Huperzine A Improves Neurological Deficits After Spontaneous Subarachnoid Hemorrhage by Inhibiting Endothelial Cell Pyroptosis
Date:
03 Jun,2024
Recently, "Huperzine A ameliorates neurological deficits after spontaneous subarachnoid hemorrhage through endothelial cell pyroptosis inhibition" was published in Acta Biochimica et Biophysica Sinica. The study was conducted by a team from the Department of Neurosurgery and the Health Checkup Center at Hangzhou First People's Hospital, affiliated with the School of Medicine at Westlake University. The study shows that huperzine A injection can inhibit endothelial cell pyroptosis, combat oxidative stress, and improve early brain injury following subarachnoid hemorrhage (SAH).
Background Introduction
Subarachnoid hemorrhage (SAH) is a severe type of stroke [1,2], primarily caused by aneurysm rupture, and is characterized by high rates of morbidity and mortality [3]. Moreover, survivors often experience cognitive impairments that significantly impact their daily functioning, work capacity, and overall quality of life [4]. Early brain injury occurring within the first 72 hours is widely recognized as the main contributor to the poor prognosis observed in SAH patients [5]. Reducing early brain damage not only improves survival rates but also enhances the long-term outcomes for SAH patients [6,7]. Therefore, preventing early brain injury in SAH patients represents a crucial therapeutic strategy aimed at improving their overall prognosis. It has been shown that neuronal apoptosis and blood-brain barrier (BBB) disruption are hallmark events associated with early brain injury following SAH. These processes are closely linked to irreversible acute brain damage after SAH and play a significant role in determining the poor prognosis experienced by many patients [8,9]. Additionally, increased BBB permeability allows immune molecules to infiltrate the brain parenchyma, further exacerbating brain injury. As such, inhibiting BBB dysfunction is considered a promising approach to effectively mitigate early brain injury after SAH, making it a key therapeutic method for enhancing patient outcomes and improving prognosis.
Subarachnoid hemorrhage (SAH) is a severe type of stroke [1, 2], primarily caused by the rupture of intracranial aneurysms, and is characterized by high rates of disability and mortality [3]. Moreover, survivors often experience cognitive impairments that significantly impact their daily functioning, work capacity, and quality of life [4]. Early brain injury occurring within 72 hours after SAH is widely recognized as one of the key factors contributing to poor patient outcomes [5]. Reducing this early brain damage not only enhances survival rates but also improves long-term prognosis for SAH patients [6, 7]. Therefore, mitigating early brain injury in SAH patients represents a crucial therapeutic strategy for optimizing their overall prognosis. Research has shown that neuronal apoptosis and blood-brain barrier (BBB) disruption are hallmark events in the early stages of SAH-induced brain injury, closely linked to irreversible acute brain damage following SAH—and serve as major determinants of unfavorable patient outcomes [8, 9]. Additionally, increased BBB permeability allows immune molecules to migrate into the brain parenchyma, further exacerbating tissue damage. Studies indicate that inhibiting BBB dysfunction can effectively alleviate early brain injury after SAH, making it a vital approach to improving patient outcomes.
Materials and Methods
Animal handling
SPF male SD rats were fed according to a standard animal care protocol. After a one-week adaptation period, the following treatments were administered: (1) Sham group: SD rats underwent a sham surgery; (2) Model group: SD rats were subjected to SAH and received an intraperitoneal injection of saline; and (3) Treatment group: SD rats with SAH were treated with Huperzine A (0.1 mg/kg, WEPON, Drug Approval Number: H20183340), also administered via intraperitoneal injection. The procedure was conducted as follows: After the SD rats were anesthetized, 0.35 mL of fresh autologous blood (collected over 20 seconds) without heparin was slowly injected into the anterior cistern near the optic chiasm. The animals were then kept in a head-down position at 30°C for 20 minutes. Immediately afterward, they were injected with 2 mL of normal saline and returned to their cages individually. Body temperature was maintained at 37°C throughout the experiment. In the sham group, male SD rats weighing 250–300 g received an intraperitoneal injection of normal saline instead of autologous blood. In both the model and treatment groups, the placebo (saline) or Huperzine A was administered intraperitoneally 12 hours after the autologous blood injection.
SPF male SD rats were housed according to a standard animal care protocol. After a one-week acclimatization period, the following procedures were performed: (1) Sham-operated group: SD rats underwent a sham surgical procedure; (2) Model group: SD rats were induced with subarachnoid hemorrhage (SAH), followed by intraperitoneal injection of normal saline; (3) Treatment group: SD rats were subjected to SAH induction and then received an intraperitoneal injection of huperzine A (0.1 mg/kg, provided by Wanbangde Pharmaceutical Group Co., Ltd., Drug Approval No.: H20183340). The experimental steps are as follows: After anesthesia, fresh autologous blood without heparin was slowly injected into the pre-chiasmatic cistern over 20 seconds at a volume of 0.35 mL. The animals were kept with their heads tilted downward at 30°C for 20 minutes. Immediately afterward, 2 mL of normal saline was administered, and the rats were returned individually to their cages, with body temperature maintained at 37°C. In the sham-operated group, male SD rats weighing 250–300 g received an intraperitoneal injection of normal saline instead of autologous blood. In both the model and treatment groups, rats were given either a placebo (normal saline) or huperzine A via intraperitoneal injection, respectively, 12 hours after the autologous blood injection.
Research findings
1. Huperzine A improves neurological deficits and reduces neuronal apoptosis in brain tissue of SAH rats.
2. Huperzine A inhibits BBB dysfunction by improving the expression of tight junction proteins in SAH rats.
3. Huperzine A improved pyroptosis in endothelial cells of brain tissue in SAH rats.
4. Huperzine A improved oxidative stress in the brain tissue of SAH rats and inhibited endothelial cell pyroptosis mediated by oxidative stress.
5. Huperzine A inhibits the activation of the NF-κB pathway in endothelial cells of brain tissue in SAH rats.
Conclusion: Plant-derived huperzine A exerts neuroprotective effects in obesity-related cognitive impairment [32], Alzheimer’s disease and other forms of dementia [33], as well as in repetitive traumatic brain injury [34]. In this study, we found that huperzine A significantly improved both the neurological deficit scores and balance assessments in rats subjected to SAH. Notably, huperzine A’s ability to ameliorate neuronal damage has been linked to its inhibitory effect on neuronal apoptosis [17, 18]. Consistent with these findings, our research revealed that huperzine A markedly reduced levels of neuronal apoptosis in brain tissue following SAH. These results suggest that huperzine A not only suppresses neuronal cell death but also helps mitigate early neurological deficits after SAH. Importantly, huperzine A has already been demonstrated to be safe in multiple clinical studies. This study further underscores huperzine A’s neuroprotective role in neurological disorders, offering a promising new therapeutic approach for addressing early brain injury following SAH.
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