Proapoptotic and prepulse inhibition (PPI) disrupting effects of Hypericum perforatum in rats.
ABSTRACT St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects.
Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders.
The effects of acute (500 mg/kg) and chronic (200mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas.
Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit.
The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.
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ABSTRACT: Hyperforin is a plant derived antibiotic from St. John's wort. Here we describe a novel activity of hyperforin, namely its ability to inhibit the growth of tumour cells by induction of apoptosis. Hyperforin inhibited the growth of various human and rat tumour cell lines in vivo, with IC(50) values between 3-15 microM. Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-specific morphological changes. In MT-450 mammary carcinoma cells hyperforin increased the activity of caspase-9 and caspase-3, and hyperforin-mediated apoptosis was blocked by the broad-range caspase inhibitor zVAD.fmk. When added to MT-450 cells, hyperforin, but not paclitaxel, induced a rapid loss of the mitochondrial transmembrane potential Deltapsi(m), and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Deltapsi(m) revealed that the hyperforin-mediated mitochondrial permeability transition can not be prevented by zVAD.fmk. This indicates that mitochondrial permeabilization is a cause rather than a consequence of caspase activation. Moreover, hyperforin was capable of releasing cytochrome c from isolated mitochondria. These findings suggest that hyperforin activates a mitochondria-mediated apoptosis pathway. In vivo, hyperforin inhibited the growth of autologous MT-450 breast carcinoma in immunocompetent Wistar rats to a similar extent as the cytotoxic drug paclitaxel, without any signs of acute toxicity. Owing to the combination of significant antitumour activity, low toxicity in vivo and natural abundance of the compound, hyperforin holds the promise of being an interesting novel antineoplastic agent that deserves further laboratory and in vivo exploration.Oncogene 03/2002; 21(8):1242-50. · 7.36 Impact Factor
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ABSTRACT: Hyperforin (HP) is an abundant component of St John's wort with antibiotic and antidepressive activity. We report here the ability of HP and that of polyphenolic procyanidin B2 (PB-2) to inhibit the growth of leukemia K562 and U937 cells, brain glioblastoma cells LN229 and normal human astrocytes. HP inhibited the growth of cells in vitro with GI(50) values between 14.9 and 19.9 microM. The growth inhibitory effect of PB-2 was more pronounced in leukemia cell lines K562 and U937, the GI(50) concentrations being about 12.5 microM established after 48 h incubation differed significantly (P<0.05) from those of LN229 and normal human astrocytes (103.1 and 96.7 microM), respectively. Further, HP and hypericin (HY) (a naphthodianthrone from St John's wort) acted synergistically in their inhibitory effect on leukemic (K562, U937) cell growth. Cell death occurred after 24 h treatment with HP and PB-2 by apoptosis. A dose-dependent loss of membrane phospholipid asymmetry associated with apoptosis was induced in all cell lines as evidenced by the externalization of phosphatidylserine (PS) and morphological changes in cell size and granulosity by scatter characteristics. In leukemia U937 cells, HP increased the activity of caspase-9 and caspase-3 and in K562 cells caspase-8 and caspase-3. In addition, the broad spectrum caspase inhibitor z-VAD-fmk inhibited both the appearance of PS exposure and the activation of caspases, illustrating the functional relevance of caspase activation during HP-induced apoptosis. Cytocidal effects of HP and its cooperation with HY on tumor growth inhibition in a synergistic manner make the St John's wort an interesting option in cancer warranting further in vitro and in vivo investigation.European Journal of Pharmaceutics and Biopharmaceutics 07/2003; 56(1):121-32. · 3.83 Impact Factor
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ABSTRACT: Hyperforin, a phloroglucinol derivative found in Hypericum perforatum (St. John's wort) extracts has antidepressant properties in depressed patients. Hyperforin has a unique pharmacological profile and it inhibits uptake of biogenic monoamines as well as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by hyperforin is related to its ability to dissipate the pH gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In the present study we demonstrate that hyperforin induces dose-dependent efflux of preloaded [3H]5HT and [3H]DA from rat brain slices. Moreover, we show that hyperforin attenuates depolarization- dependent release of monoamines, while increasing monoamine release by amphetamine or fenfluramine. It is also demonstrated that preincubation of brain slices with reserpine is associated with dose- dependent blunting of efflux due to hyperforin. Our data indicate that hyperforin-induced efflux of [3H]5HT and [3H]DA reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines.Life Sciences 11/2004; 75(23):2841-50. · 2.56 Impact Factor