BILOBALIDE AND NEUROPROTECTION

doi:10.1016/S1043-6618(02)00233-5

Pharmacological Research

Volume 46, Issue 6, December 2002, Pages 565-568

https://doi.org/10.1016/S1043-6618(02)00233-5 Get rights and content

Abstract

In vivo studies have indicated that systemically administered bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, can reduce cerebral edema produced by triethyltin, decrease cortical infarct volume in certain stroke models, and reduce cerebral ischemia. In vitro and ex vivo studies indicate that bilobalide has multiple mechanisms of action that may be associated with neuroprotection, including its preservation of mitochondrial ATP synthesis, its inhibition of apoptotic damage induced by staurosporine or by serum-free medium, its suppression of hypoxia-induced membrane deterioration in the brain, and its actions of increasing the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome c oxidase and the ND1 subunit of NADH dehydrogenase. As multiple modes of action may apply to bilobalide, it could be useful in developing therapy for disorders involving cerebral ischemia and neurodegeneration.

Section snippets

INTRODUCTION

Extracts of Ginkgo biloba leaves are widely used to treat cerebrovascular and peripheral vascular insufficiency, symptoms associated with dementia, and the cognitive decline and neurosensory impairments that may be associated with aging and senility. These extracts, when adequately standardized, contain about 24% flavonoid glycosides, about 6% terpene trilactones (ginkgolides, bilobalide), about 7% proanthocyanidins, and certain low molecular weight organic acids. Bilobalide accounts for about

EFFECTS OF BILOBALIDE ON CEREBRAL EDEMA AND CEREBRAL ISCHEMIA

Early observations indicated that administration of a Ginkgo extract, termed ‘EGb 761’, can prevent cytotoxic brain edema induced by triethyltin in rats, and that this effect was associated with its bilobalide constituent [1], [2]. In light of more recent results ([3], [4]; see the following description), it is now considered that the mechanism underlying such anti-edema effects of bilobalide involves its action of preventing the uncoupling of oxidative phosphorylation (OXPHOS) and its

PRESERVATION OF MITOCHONDRIAL FUNCTION BY BILOBALIDE

Janssens et al. [3] have shown that bilobalide can inhibit hypoxia-induced decreases in ATP content in vascular endothelial cells. This effect was probably related to an increase in cellular respiratory efficiency, as indicated by their ex vivo findings that oral treatments of rats with bilobalide increased the RCR of mitochondria isolated from liver. It was concluded that since ischemia is known to uncouple OXPHOS, the action of bilobalide of protecting against hypoxia-induced decreases in ATP

BILOBALIDE AND CELL SURVIVAL

Addition of bilobalide (10 μM) to the bathing medium protected hippocampal neurons cultured from newborn rats against excitotoxic damage ([5]; see also [9]). Pretreatment of neurons cultured from chick telencephalon with bilobalide (0.1 μM) provided significant protection against hypoxic damage [5], [10].

More recently, Ahlemeyer et al. [11] found that the increase in apoptotic chick embryonic neurons caused by exposure to 24 h of serum deprivation could be reduced to control level by bilobalide (1 μ

BILOBALIDE AND GENE EXPRESSION

To date, only a few studies concerning bilobalide and gene expression have been reported. With regard to mitochondrial OXPHOS, the study of Chandrasekaran et al. [16], conducted with a morphological variant of rat PC12 cells that had been differentiated with nerve growth factor, showed that addition of bilobalide (15.3 or 30.6 μM) but not ginkgolide B (11.8 or 23.6 μM) to the culture medium increased the mRNA level of the mitochondrial DNA (mtDNA)-encoded COX III subunit of cytochrome c oxidase

SYNTHETIC BILOBALIDE DERIVATIVES

To date, two studies have dealt with synthetic bilobalide derivatives. Ahlemeyer et al. [21] found that 4-hydroxy-4-tert-butyl-2,3,5,6-tetrahydrothiopyran-1-oxide (NV-31; 1–100 nM) protected neurons that were cultured from chick embryo telencephalon against apoptotic damage induced by serum deprivation or by exposure to staurosporine in a concentration-dependent manner. NV-31 (100 nM) also decreased staurosporine-induced neuronal damage in mixed cultures of neurons and astrocytes of neonatal rat

CONCLUDING COMMENTS

Evidence which has accumulated during the last few years indicates that bilobalide may have neuroprotective effects. Further studies seem warranted to determine its possible usefulness in developing therapy for disorders involving cerebral ischemia and neurodegeneration.

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Chatterjee SS, Gabard BL, Jaggy HEW. Pharmaceutical compositions containing bilobalid for the treatment of...

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Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide
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Citation Excerpt :
Bilobalide is an important sesquiterpene in GBE. Due to its significant anti-ischemic and neuroprotective effects [19–23], it can be used to prevent and treat IHD [19], stroke [20], and Alzheimer's disease [21]. It has been reported that bilobalide has a protective effect on the mitochondria [19,20,22,23], including the protection of complex I and III activities [19,23], preservation of mitochondrial ATP synthesis [20], and increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome C oxidase and ND1 subunit of NADH dehydrogenase [22].
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Pharmacological Research

Abstract

Section snippets

INTRODUCTION

EFFECTS OF BILOBALIDE ON CEREBRAL EDEMA AND CEREBRAL ISCHEMIA

PRESERVATION OF MITOCHONDRIAL FUNCTION BY BILOBALIDE

BILOBALIDE AND CELL SURVIVAL

BILOBALIDE AND GENE EXPRESSION

SYNTHETIC BILOBALIDE DERIVATIVES

CONCLUDING COMMENTS

References (22)

Protection of hypoxia-induced ATP decrease in endothelial cells by Ginkgo biloba extract and bilobalide

Biochem. Pharmacol.

Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba

Brain Res.

Neuroprotective effects of Ginkgo biloba constituents

Eur. J. Pharm. Sci.

Protection of mitochondrial respiration activity by bilobalide

Biochem. Pharmacol.

Testing drug effects against hypoxic damage of cultured neurons during long-term recovery

Life Sci.

Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents

Eur. J. Pharmacol.

Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia

Brain Res.

Inhibition by ginkgolides and bilobalide of the production of nitric oxide in macrophages (THP-1) but not in endothelial cells (HUVEC)

Biochem. Pharmacol.

Neuroprotective effects of NV-31, a bilobalide-derived compound: evidence for an antioxidative mechanism

Brain Res.

Mitochondrial respiratory chain as a new target for anti-ischemic molecules

Eur. J. Pharmacol.

Cited by (114)

Current biomarkers and treatment strategies in Alzheimer disease: An overview and future perspectives

Efficacy and safety of standardized Ginkgo biloba extract as adjuvant therapy for intracerebral hemorrhage in China: A systematic review and meta-analysis

An update on the novel and approved drugs for Alzheimer disease

Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide

Progress in the Total Synthesis of Natural Products Embodying Diverse Furofuranone Motifs: A New Millennium Update

Identification of the main active antidepressant constituents in a traditional Turkish medicinal plant, Centaurea kurdica Reichardt