Salvia miltiorrhiza Alleviates Memory Deficit Induced by Ischemic Brain Injury in a Transient MCAO Mouse Model by Inhibiting Ferroptosis

Abstract

Salvia miltiorrhiza (SM) has been used in oriental medicine for its neuroprotective effects against cardiovascular diseases and ischemic stroke. In this study, we investigated the therapeutic mechanism underlying the effects of SM on stroke using a transient middle cerebral artery occlusion (tMCAO) mouse model. Our results showed that SM administration significantly attenuated acute brain injury, including brain infarction and neurological deficits, 3 days after tMCAO. This was confirmed by our magnetic resonance imaging (MRI) study, which revealed a reduction in brain infarction with SM administration, as well as our magnetic resonance spectroscopy (MRS) study, which demonstrated the restoration of brain metabolites, including taurine, total creatine, and glutamate. The neuroprotective effects of SM were associated with the reduction in gliosis and upregulation of inflammatory cytokines, such as interleukin-6 (IL-6) and Tumor necrosis factor-α (TNF-α), along with the upregulation of phosphorylated STAT3 in post-ischemic brains. SM also reduced the levels of 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), which are markers of lipid peroxidation, induced by oxidative stress upregulation in the penumbra of the tMCAO mouse brain. SM administration attenuated ischemic neuronal injury by inhibiting ferroptosis. Additionally, post-ischemic brain synaptic loss and neuronal loss were alleviated by SM administration, as demonstrated by Western blot and Nissl staining. Moreover, daily administration of SM for 28 days after tMCAO significantly reduced neurological deficits and improved survival rates in tMCAO mice. SM administration also resulted in improvement in post-stroke cognitive impairment, as measured by the novel object recognition and passive avoidance tests in tMCAO mice. Our findings suggest that SM provides neuroprotection against ischemic stroke and has potential as a therapeutic agent.

Current evidence of synaptic dysfunction after stroke: Cellular and molecular mechanisms

“…In several recent studies, Salvia miltiorrhiza (SM) was shown to alleviate synaptic deficits and neuronal loss in a transient MCAO mouse model. 127 Rhynchophylline attenuates sensorimotor deficits, alleviates hippocampus-dependent spatial memory injury, and reduces infarct volume in mice that undergo MCAO. In addition, rhynchophylline administration ameliorates the loss of synaptophysin I and improves dendritic complexity, dendritic spine density, and synaptic plasticity in mice that undergo MCAO.…”

“…In several recent studies, Salvia miltiorrhiza (SM) was shown to alleviate synaptic deficits and neuronal loss in a transient MCAO mouse model 127 . Rhynchophylline attenuates sensorimotor deficits, alleviates hippocampus‐dependent spatial memory injury, and reduces infarct volume in mice that undergo MCAO.…”

Recent advances in potential therapeutic targets of ferroptosis‑associated pathways for the treatment of stroke (Review)

“…It is well established that TCM herbs have antioxidant, anti-inflammatory and blood-brain barrier-protective effects, and that they can prevent stroke in advance by various means ( 179 – 181 ). For example, Danhong injection, a standardized injection comprising danshen ( Salvia miltiorrhiza ) and saffron, has been shown in studies to improve ferroptosis in ischemic stroke ( 182 , 183 ). In addition, moxibustion (a form of therapy that entails the burning of mugwort leaves), as one of the more frequently used treatments, has an important role in the treatment of cerebral infarction.…”

Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke

“…Treatment against ischemic stroke by targeting ferroptosis has gained much attention. 192 Vitexin, 193 Angong Niuhuang Wan, 194 selenium, 195 Srs11‐92, 196 Se‐methyl L‐selenocysteine, 197 Rehmannioside A, 166 Icariside II, 198 Galangin, 199 Carvacrol, 200 Carthamin yellow, 201 β‐Caryophyllene, 202 Astragaloside IV, 203 Salvia miltiorrhiza, 204 Naotaifang extract, 133 Naotaifang, 205 Baicalein, 154 Caffeic acid, 206 Danlou tablet, 207 Rhein, 208 HSYA and AHSYB, 209 Calycosin, 159 Ferrostatin‐1, 210 Compound Tongluo Decoction, 211 Loureirin C, 212 Edaravone, 191 Quercetin, 213 Cottonseed oil, 214 DHT, 215 Dl‐3‐n‐butylphthalide, 216 Dimethyl fumarate, 217 2‐(1‐(4‐(4‐methylpiperazin‐1‐yl)phenyl)ethyl)‐10H‐phenothiazine, 218 Kaempferol, 219 Danhong injection, 220 Neutral polysaccharide from Gastrodia elata , 221 Resveratrol 190 alleviate injury after IS by inhibiting ferroptosis (Table 1 ).…”