Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia

Martins, Ana; Hu, Jing; Mu, Chaofeng; Álvarez, Pedro; Ford, Byron D.; Sayed, K. El; Eterović, Vesna A.; Ferchmin, P.A.; Hao, Jiukuan

doi:10.1016/j.neuroscience.2015.02.001

Cited by 47 publications

(47 citation statements)

References 37 publications

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“…At present, animal models of cerebral ischemia have mainly been developed in rodents34. However, the differences between humans and rodents—particularly in terms of genetics, pathology and pharmacology— significantly limits the use of rodent models of stroke in the development of neuroprotective therapies.…”

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confidence: 99%

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

Dai

Huang

et al. 2017

Sci Rep

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Endothelin-1 (ET-1), a vasoconstrictor, has recently been used to induce focal ischemia in rodents and marmoset monkeys. The rhesus monkey, however, has numerous advantages to the rodent and marmoset that make it a superior and irreplaceable animal model for studying stroke in the brain. In the present study, after mapping the preferred hand representation in two healthy male monkeys with intracortical micro-stimulation, ET-1 was microinjected into the contralateral motor cortex (M1) to its preferred hand. The monkeys had been trained in three manual dexterity tasks before the microinjection and were tested for these tasks following the ET-1 injection. Brain Magnetic Resonance Imaging scans were performed 1, 7, 14 and 28 days post ischemia. It was found that ET-1 impaired the manual dexterity of the monkeys in the vertical slot and rotating Brinkman board tasks 3–8 days after the injection. Brain imaging found that severe edema was present 7 days after the focal ischemia. This data suggest that ET-1 can induce transient ischemic stroke in rhesus monkey and that ET-1 induced focal ischemia in non-human primates is a potential model to study the mechanism of stroke and brain repair after stroke.

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confidence: 99%

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

Dai

Huang

et al. 2017

Sci Rep

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“…As 1 is known to possess a variety of biological activities, both oxidized derivatives 4 a , b may have new or enhanced biological activities, which will be investigated in further studies. The two‐step, chemo‐, regio‐, and stereoselective hydroxylation of 1 described here highlights its usefulness for the biomimetic oxidation of terpenes .…”

Section: Discussionmentioning

confidence: 99%

“…Compound 1 is a noncompetitive inhibitor of nicotinic acetylcholine receptors and has already tested positively as a neuroprotective drug against the neurotoxic effect of the organophosphate diisopropylfluorophosphate . Furthermore, the neuroprotective effect of 1 was also demonstrated in rodent ischemic stroke models . As a result of their pharmaceutical potential, cembranoids have been described as promising lead compounds .…”

Section: Introductionmentioning

confidence: 93%

“…[13] Furthermore,t he neuroprotective effect of 1 was also demonstrated in rodent ischemic stroke models. [14] As ar esult of their pharmaceutical potential, cembranoids have been described as promising lead compounds. [15] Oxidized derivatives of 1 have been synthesized CytochromeP 450 monooxygenases( P450s) are involved in the biosynthesis of aw ide range of bioactive secondary metabolites.…”

Section: Introductionmentioning

confidence: 99%

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One‐Pot, Two‐Step Hydroxylation of the Macrocyclic Diterpenoid β‐Cembrenediol Catalyzed by P450 BM3 Mutants

et al. 2016

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Cytochrome P450 monooxygenases (P450s) are involved in the biosynthesis of a wide range of bioactive secondary metabolites. They often introduce several oxy functionalities at different positions of a substrate through multiple steps and produce a range of oxidized derivatives. Herein, we describe a one‐pot two‐step hydroxylation of the diterpenoid β‐cembrenediol isolated from the plant Nicotiana tabacum. This 14‐membered macrocycle shows neuroprotective effects and is, along with its oxidized derivatives, of pharmaceutical interest. Sequential hydroxylations catalyzed by the regioselective P450 BM3 mutants F87A/I263L and V78A/F87G yielded the epimeric (9S,10R/S)‐β‐cembrenetetraols with a diastereomeric ratio of 48:52. The replacement of the mutant V78A/F87G with L75A/V78A/F87G in the second step improves the diastereomeric ratio up to 10:90. Absolute configurations of the newly introduced hydroxy groups were determined by quantum‐mechanical calculations of NMR spectra.

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“…There is still limited available drug treatment for stroke, and the state and extent of knowledge and treatment of ischemic brain injury is inadequate. Therefore, therapeutic strategies are being explored to improve functional outcome after stroke injury [5, 6]. Redox disequilibrium, disruption of ionic homeostasis, lactic acidosis and defects in neurotransmitter metabolism are critical aspects of cerebral ischaemia/reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

Improvement of 2-Vessel Occlusion Cerebral Ischaemia/Reperfusion-Induced Corticostriatal Electrolyte and Redox Imbalance, Lactic Acidosis and Modified Acetylcholinesterase Activity by Kolaviron Correlates with Reduction in Neurobehavioural Deficits

et al. 2017

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Background: Disruption of electrolyte, redox and neurochemical homeostasis alongside cellular energy crisis is a hallmark of cerebral ischaemia and reperfusion injury. Purpose: This study investigated the effect of kolaviron (KV) on cortical and striatal cation imbalance, oxidative stress and neurochemical disturbances as well as neurobehavioural deficits in animals subjected to bilateral common carotid artery occlusion (BCCAO)-induced ischaemia/reperfusion injury. Methods: KV was administered at a dose of 100 or 200 mg/kg to male Wistar rats 1 h before a 30 min BCCAO/4 h reperfusion (I/R). This was followed by neurobehavioral assessment and biochemical evaluations of cation levels, oxidative stress indicators, lactate dehydrogenase activity and acetylcholinesterase (AChE) activity in the brain of animals. Conclusion: KV significantly restored altered cortical and striatal Ca²⁺, Na⁺, K⁺ and Mg²⁺ levels, ameliorated redox imbalance, lactic acidosis and modified AChE activity caused by I/R injury. The favourable neurobehavioural effects of KV correlated with biochemical outcomes. The pharmacological potential of KV in the treatment and management of ischemic stroke and allied pathological conditions via multiple targets (neurotransmitter metabolism, bioenergetic failure and ionic homeostasis) is highlighted by the study.

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Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia

Cited by 47 publications

References 37 publications

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

One‐Pot, Two‐Step Hydroxylation of the Macrocyclic Diterpenoid β‐Cembrenediol Catalyzed by P450 BM3 Mutants

Improvement of 2-Vessel Occlusion Cerebral Ischaemia/Reperfusion-Induced Corticostriatal Electrolyte and Redox Imbalance, Lactic Acidosis and Modified Acetylcholinesterase Activity by Kolaviron Correlates with Reduction in Neurobehavioural Deficits

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