A novel caffeoyl triterpene attenuates cerebral ischemic injury with potent anti‐inflammatory and hypothermic effects

Abstract

Despite the intense efforts in searching for stroke therapies, an urgent need still exists to explore novel neuroprotective agents for ischemic stroke that have high efficacy and wide therapeutic time-window. Here, we provide the first demonstration that 28-O-caffeoyl betulin (B-CA), a novel derivative of naturally occurring caffeoyl triterpene, could significantly alleviate brain infarction and neurological deficit when given as late as 6 h after transient middle cerebral artery occlusion in the rat. Moreover, post-ischemia B-CA administration exhibited long-term (14 days post stroke) protective effects on both brain infarction and functional (i.e., motor and sensory) deficits. Protective B-CA effects correlated with decreased inflammatory responses as indicated by inhibition of microglia and astrocyte activation [stained with ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) antibody, respectively], as well as suppression of tumor necrosis factor-a, interleukin-1b, and cyclooxygenase-2 overproduction in the ipsilateral cortex of ischemic rat. B-CA administration caused significant hypothermia in the focal cerebral ischemic rat, which may contribute to its ameliorative effects on brain damage and inflammation. In view of its potency in wide therapeutic time-window, robust anti-inflammatory and hypothermic effects, this novel caffeoyl triterpene derivative may lead toward the development of effective therapeutic strategies for the treatment of ischemic stroke. Keywords: caffeoyl triterpene, hypothermia, inflammation, ischemic stroke, neuroprotection, therapeutic time window. Ischemic stroke is one of the leading causes of morbidity and mortality in the world (Go et al. 2014). Currently, the only US Food and Drug Administration-approved acute intervention for ischemic stroke is thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA). Although rt-PA treatment can provide acute recanalization and improves functional outcome post stroke, it has a narrow therapeutic time window of < 4.5 h post stroke with risk of hemorrhage and may exacerbate the cerebral injury (Fonarow et al. 2011). While on the other hand, the neuroprotective approach has gained increasing attention and considered as a promising alternative treatment for ischemic stroke (Schmidt Abbreviations used: B-CA, 28-O-caffeoyl betulin; COX-2, cyclooxygenase-2; ERK, extracellular regulated protein kinases; GFAP, glial fibrillary acidic protein; Iba-1, ionized calcium-binding adapter molecule 1; IL-1b, interleukin-1b; IL-6, interleukin-6; MCAO, middle cerebral artery occlusion; MMP-9, matrix metallopeptidase 9; mNSS, modified neurological severity score; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; OGD, oxygen and glucose deprivation; PSD-95, postsynaptic density 95; rCBF, regional cerebral blood flow; rt-PA, recombinant tissue plasminogen activator; TNF-a, tumor necrosis factor-a; TRPV1, the transient receptor potential cation channel subfamily V member 1; TTC, tri...

Neuroprotective Phytochemicals in Experimental Ischemic Stroke: Mechanisms and Potential Clinical Applications

“…Triterpenoid saponins, the glycosides of triterpenoids, are an important form of the bioactive triterpenoids. In total, 20 triterpenoids are found to exhibit neuroprotection in ischemic stroke including arjunolic acid [357], asiatic acid [358,359], boswellic acids [81,360,361], 28-O-caffeoyl betulin [362], celastrol [73,363], echinocystic acid [364], 18β-glycyrrhetinic acid [365], maslinic acid [366], ursolic acid [367], and triterpenoid glycosides: madecassoside [368], astragaloside IV [62,114,369,370], glycyrrhizin [91,[371][372][373], diammonium glycyrrhizinate [374], ginsenoside Rb1 [34,55,115,375,376], ginsenoside Rd [49,[377][378][379][380][381][382][383], ginsenoside Rg1 [384][385][386][387][388][389], ginsenoside Rg3 [390], pseudoginsenoside F11 [391,…”

Caffeoyl Triterpenoid Esters as Potential Anti-ischemic Stroke Agents from Celastrus orbiculatus

“…After 24 h of reperfusion, the neurological deficits were tested according to the modified Neurological Severity Score (mNSS) evaluations . The mNSS was scored on an 18-point scale including motor, visual, and tactile responses . A higher score represents worse neurological performance.…”

A new insight into the ability to resist Ischemic brain injury: Does hibernation matter?

“…This uncontrolled cascade of cellular events leads to permanent neurological damage resulting in high rates of disability and death among stroke patients (Ruan et al . ). Interestingly, Bhowmick and his colleagues show that the ability of hippocampal neurons of AGS to resists OGD injury is not because of enhanced energy conservation.…”