Other Anti Ischemic Effects

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Recent studies using gerbils, mice and rats have provided some insight into the beneficial action of EGb. In experimentally induced cerebral ischemia, a 7-d treatment reduced the degree of CNS damage induced by middle cerebral artery liga-tion [46,47]. In a similar ischemia paradigm, other investigators found that EGb protected against neuronal death in the hippocampal CA1 area of the gerbil brain [15]; a follow-up study revealed that the protection extended to cells in the frontal lobe [47]. In addition, using an Alzheimer's mutant mouse model (Tg2576), EGb treatment for 6 months markedly improved spatial cognitive performance, without affecting central P-amyloid concentrations [48]. It was found that EGb could increase the rat cerebral blood flow [49] and improved ischemic memory impairment in mice [50]. Several lines of evidence suggest that EGb alleviates the subcellular damage of cerebral ischemia [51] and allows mitochondria to maintain their respiratory activity under ischemic conditions [44]. EGb may play a protective role in the homeostasis of inflammation and oxidative stress and in the prevention of cell membrane damage caused by free radicals and neurotransmission modulation [1]. As shown by Ni et al. [27], EGb761 can prevent hydroxyl-radical-induced apoptosis in cultured neurons. EGb could prevent and treat acute cerebral ischemia damage. Regarding Egb-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase [1]. It is clear that an irreversible block of protein synthesis in the selectively vulnerable CA1 field of the hippocampus necessarily leads to the death of neurons. However, the prevention of persistent inhibition of translation does not assure survival of CA1 neurons [32]. Mechanisms allowing neurons to survive, obviously including remodulation of gene expression, have not been clear until now. EGb, with its ability to protect translational machinery, permits newly synthesized mRNAs to be translated into functional proteins, thus allowing the altered gene expression to be effective.

The antiedema effect of EGb is one aspect of its potential therapeutical effects that has not been widely investigated. The first indication of inhibition of toxic edema formation in white matter induced by neurotoxic triethyltin was presented as early as 1986 by Otani [52], and later works proved the beneficial effect of EGb on cerebral edema induced also by bromethalin, a toxin [53], and by hyperther-mia [54]. From all constituents of EGb, Ginkgolide B was suggested as an active factor. In a very recent study by Mdzinarishvili et al. [55], the antiedema effect of bilobalide, another EGb constituent, was tested in both in vitro (oxygen-glucose deprivation on hippocampal slices) and in vivo (middle cerebral artery occlusion in mice) conditions. Pretreatment of mice with bilobalide (10mg/kg i.p.) not only reduced the infarct area by 43% [as judged by 2,3,5-triphenyltetrazolium chloride (TTC) staining] and edema formation by 70%, but it also reduced forebrain water content in the ischemic hemisphere by 57%.

However, as the authors showed by measurement of the water content, bilobalide does not seem to block water transport and its effect is selective for edema formation induced by ischemia. The molecular mechanism of the antiedema effect of bilob-alide might involve the described protection of mitochondrial energetics and Na+, K+-ATPase activity under ischemic conditions [56, 57] or via bilobalide's interference with chloride fluxes [58]. Additionally, bilobalide increases the expression of glial growth factors in astroglial cultures, and thus astrocytes, with their contribution to tissue swelling, may be the potential targets of bilobalide [59].

Although the mechanism of EGb761 is unclear, it is possible that its actions are related to mitochondria and apoptosis because earlier studies found that caspase expression was altered [46, 60]. This is potentially important since mitochondria play a pivotal role in apoptosis for both intrinsic and extrinsic pathways [61]. The intrinsic and extrinsic pathways do not occur independently in vivo but are linked at different points, one of which is the bax/bcl-2 complex - an apoptotic to anti-apoptotic index [62]. Oligomerization of bax facilitates its insertion into the outer mitochondrial membrane, triggering cytochrome c release, which promotes apop-tosis. Conversely, bcl-2 forms complexes with bax in such a way that the release of cytochrome c is inhibited to prevent apoptosis. Therefore, the ratio of bax/bcl-2 is crucial in determining the progress of cell apoptosis for both the intrinsic and extrinsic pathways [62]. At least two studies, by Lu et al. [63] and Loh et al. [64], corroborate the assumption of a mitochondria-based antiapoptotic protective effect of EGb. Lu et al. [63] investigated the levels of apoptotic markers in six brain regions following induced global ischemia in senescence-accelerated mice (SAMP8). A 4-d treatment with EGb significantly decreased bax/bcl-2 ratios in all brain regions in both young (1-month-old) and aged (16-month-old) mice, and the authors suggest that the bax/bcl-2 ratio provides a suitable index of apoptosis, and modulation of these markers may explain the neuroprotective action of EGb761. Interestingly, the beneficial action of EGb was efficacious despite the accelerated aging process in the animals, and future studies of the bax/bcl-2 ratio in the brain of animals and humans should be conducted. Since the protective effect of EGb761 was regional as well as global in both aged (16-month-old) and young (1-month-old) mice, this could explain why EGb761 showed protective effects for different neurological diseases such as Parkinson's [65] and Alzheimer's [66] diseases, which involves different brain areas. The remarkable cerebral protection of EGb was comapared with the antihypertensive Losartan on stroked rats. Both agents were administrated orally (EGb = 50mg/kg/d) 1 week before stroke induction by middle cerebral artery occlusion. Both the mRNA and protein levels of pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-xS) showed significant reduction in both pretreatments comparing to the vehicle group. In addition, the decrease in the number of apoptotic cells identified by TUNEL assay indicates a potent and promising therapeutic effect of EGb for stroke treatment, at least in animal experiments [64].

Moreover, the neuroprotective effect of EGb may be correlated with its effect on glucocorticoid synthesis - ginkgolides A and B inhibit corticosteroid synthesis and restore the ability to adapt to stress by reducing LPO and phospholipid content in the brain [67]. Another mechanism of EGb-evoked neuroprotection involves maintaining a balance between inhibitory/excitatory amino acids [68], platelet-activating factor receptor antagonism [69], the ability to inhibit NO-stimulated protein kinase C activity [29], and protection against ischemia-induced changes of Na+, K+-ATPase activity [56]. Finally, EGb protects neurons against glutamate excito-toxicity [70] and against apoptosis (cell death) induced by P-amyloid protein, a known pathogenetic factor in pathological brain ageing [71].

Bilobalide, a constituent of EGb, increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels. This metabolic result is supported by the finding that bilob-alide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase [1]. It is clear that an irreversible block of protein synthesis in the selectively vulnerable CA1 field of the hippocampus necessarily leads to the death of neurons. However, the prevention of persistent inhibition of translation does not assure survival of CA1 neurons [32]. The additional effect of EGb on MCAO-induced gap junction communication was studied on the mRNA and protein levels of connexin 43 and astrocyte gap junction intercellular communication (GJIC) induced by hypoxia-reoxygenation. Pretreatment with EGb (100mg/l) for 7 d significantly prevented the hypoxia-reoxygenation inhibition of GJIC followed by improved expression of Cx43, leading to improved neurological deficit [72]. Changes in energy-related metabolites in the striatum of gerbils subjected to focal cerebral ischemia for 60min after pretreatment with EGb761 and FK506, a calcium-dependent phosphatase calcineurin inhibitor, were investigated using mi-crodialysis. The observed decreases in glucose (10% of the baseline) and pyru-vate (20% of the baseline) and increase in lactate (60% of the baseline) during ischemia was significantly preserved by both EGb761 treatment and the combination (EGb761 and FK506) therapy, which suggets that preservation of energy metabolism during cerebral I/R may contribute to the neuroprotective effects of EGb [11].

A very important precaution with respect to the neuroprotective activity of EGb is communicated by the study of da Lima et al. [73]. These authors were not able to show a reduction in brain infarct size in rats after transient MCAO in conditions of unprevented, ischemia-induced fever. Acute (200 mg/kg) or chronic (100 mg/kg, once daily, for 14 d) treatment with EGb in combination or not with antipyretic dipyrone before ischemic insult failed to reduce the infarct size. The authors warn against having high expectations about being able to treat stroke with EGb. There is much biochemical evidence, but very few studies in animal models in vivo, which demonstrate EGb-induced neuroprotection against regional ichemic damage [74]. In this context, Liu [75], by searching relevant clinical trials (COCHRANE, PubMed, EMbase) and research registers, failed to find any convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after human stroke. High-quality and large-scale randomized controlled trials are needed to test its efficacy.

Acknowledgements This paper was supported by grants: VEGA 3380/06, MVTS COST B30 and WCE 0064/07.

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