Neuroprotective effects of SMTP‐44D in mice stroke model in relation to neurovascular unit and trophic coupling

Abstract

Stachybotrys microspora triprenyl phenol (SMTP)‐44D has both anti‐oxidative and anti‐inflammatory activities, but its efficacy has not been proved in relation to the pathological changes of neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) in ischemic stroke. Here, the present study was designed to assess the efficacies of SMTP‐44D, moreover, compared with the standard neuroprotective reagent edaravone in ischemic brains. ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, SMTP‐44D (10 mg/kg) or edaravone (3 mg/kg) was intravenously administrated through subclavian vein just after the reperfusion, and these mice were examined at 1, 3, and 7 d after reperfusion. Compared with the vehicle group, SMTP‐44D treatment revealed obvious ameliorations in clinical scores and infarct volume, meanwhile, markedly suppressed the accumulations of 4‐HNE, 8‐OHdG, nitrotyrosine, RAGE, TNF‐α, Iba‐1, and cleaved caspase‐3 after tMCAO. In addition, SMTP‐44D significantly prevented the dissociation of NVU and improved the intensity of NAGO/BDNF and the number of BDNF/TrkB and BDNF/NeuN double positive cells. These effects of SMTP‐44D in reducing oxidative and inflammatory stresses were similar to or stronger than those of edaravone. The present study demonstrated that SMTP‐44D showed strong anti‐oxidative, anti‐inflammatory, and anti‐apoptotic effects, moreover, the drug also significantly improved the NVU damage and NVTC in the ischemic brain.

Electroacupuncture on Trigeminal Nerve-Innervated Acupoints Ameliorates Poststroke Cognitive Impairment in Rats with Middle Cerebral Artery Occlusion: Involvement of Neuroprotection and Synaptic Plasticity

“…This is also consistent with some other animal experiments [ 45 , 46 ]. Meanwhile, at the downstream of the BDNF/TrkB signaling pathway, the changes in the TrkB level reflected those of BDNF in both our study and others [ 47 , 48 ]. EA/TNS was found to reverse these changes in our study, suggesting that it restores cognitive function by enhancing the BDNF/TrkB pathway to contribute to neuroprotection.…”

Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke

“…Indeed, several experiments with transient focal ischemia models demonstrated reduced levels of the following in SMTP-treated animals: (i) reactive oxygen species (ROS) [ 27 , 133 ]; (ii) markers of oxidative damage [ 24 ]; (iii) matrix metalloproteinase-9 (MMP-9) and blood–brain barrier (BBB) disruption [ 23 , 27 ]; (iv) inflammatory cytokines and neuroinflammation-related proteins [ 159 ]; and (v) hemorrhagic transformation [ 23 , 24 ]. Moreover, SMTP-44D, a non-thrombolytic but sEH-inhibitory congener, was shown to reduce oxidative damage markers and protect neurovascular units and trophic coupling from impairment in a mouse model of transient focal ischemia [ 30 ].…”

“…In process ( ii ), inhibition of C-EH-catalyzed hydrolysis of anti-inflammatory epoxy fatty acids such as epoxyeicosatrienoic acid (EET) may play a role; inhibition of N-phos may play an additional role (not shown). In process ( iii ), radical-scavenging activity inherent in the SMTP structure plays a role in the suppression of oxidative modifications of lipids, proteins, nucleic acids, and sugars [ 27 , 30 , 133 , 158 , 159 ], which are implicated in cytotoxicity, tissue damage, and inflammation. Anti-inflammatory/antioxidative effects contribute to the suppression of neuronal damage and hemorrhagic transformation ( iv ).…”

“…Subsequently, we observed an unexpected additional function of SMTP, the inhibition of soluble epoxide hydrolase (sEH), which is a key enzyme that controls inflammation [ 25 ]. Along with the radical-scavenging activity inherent in the SMTP structure, the combination of thrombolytic and anti-inflammatory actions of SMTP played a key role in the treatment of ischemic stroke in several models of rodents and monkeys [ 21 , 22 , 24 , 26 , 27 , 28 , 29 , 30 ]. One of the SMTP congeners is under clinical development: compound development code, TMS-007; phase 1 study, JapicCTI-142654; and phase 2 study, JapicCTI-183842, registered at the Japan 540 Pharmaceutical Information Center Clinical Trials Information.…”

SMTP‐44D improves diabetic neuropathy symptoms in mice through its antioxidant and anti‐inflammatory activities

“…[19] Among the SMTPs, SMTP-44D was reported to have effective antioxidant and anti-inflammatory activities. [20][21][22] However, it remains unknown whether SMTP-44D has therapeutic effects in DN or if its antioxidant and anti-inflammatory activities could improve allodynia, hyperalgesia, decrease in blood flow, delay of conduction velocity, and neurological degeneration in…”