Multi-pathway Neuroprotective Effects of a Novel Salidroside Derivative SHPL-49 Against Acute Cerebral Ischemic Injury

SHPL-49 ((2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-methoxyphenyl) butoxy) tetrahydro-2H-pyran-3,4,5-triol) is a novel glycoside derivative obtained from structural modification of salidroside, which is isolated from the medicinal plant Rhodiola rosea L. SHPL-49 was administered to rats with permanent middle cerebral artery occlusion (pMCAO) for 5 days, and it was found that SHPL-49 could alleviate the cerebral infarct volume and reduce the neurological deficit score. Moreover, the effective time window of SHPL-49 in the pMCAO model was from 0.5 to 8 h after embolization. In addition, the result of immunohistochemistry showed that SHPL-49 could increase the number of neurons in the brain tissue and reduce the occurrence of apoptosis. Morris water maze and Rota-rod experiments showed that SHPL-49 could improve neurological deficits, repair neurocognitive and motor dysfunction, and enhance learning and memory ability in the pMCAO model after 14 days of SHPL-49 treatment. Further in vitro experiments showed that SHPL-49 significantly reduced the calcium overload of PC-12 cells and the production of reactive oxygen species (ROS) induced by oxygen and glucose deprivation (OGD), and increased the levels of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the production of malondialdehyde (MDA). Furthermore, SHPL-49 could reduce cell apoptosis by increasing protein expression ratio of anti-apoptotic factor Bcl-2 to pro-apoptotic factor Bax in vitro. SHPL-49 also regulated the expression of Bcl-2 and Bax in ischemic brain tissue, and even inhibited the caspase cascade of pro-apoptotic proteins Cleaved-caspase 9 and Cleaved-caspase 3. Taken together, SHPL-49 exhibited neuroprotective effects against cerebral ischemic injury through multiple pathways, such as alleviating calcium overload, reducing oxidative stress damage, and inhibiting apoptosis.