Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.

Striking differences in proconvulsant-induced alterations of seizure threshold in two rat models.

During drug development, seizure threshold tests are widely used to identify potential proconvulsant activity of investigational drugs. The most commonly used tests in this respect are the timed intravenous pentylenetetrazole (PTZ) infusion seizure test and the maximal electroshock seizure threshold (MEST) test in mice or rats. To our knowledge, no study is available in which proconvulsant drug activities in these models are directly compared, which prompted us to perform such experiments in male Wistar rats. Five drugs with reported proconvulsant activity were tested in the two models: d-amphetamine, chlorpromazine, caffeine, theophylline, and tramadol. Furthermore, the anticonvulsant drug phenobarbital was included in the experiments. While phenobarbital exerted anticonvulsant activity in both models, the five proconvulsant drugs markedly differed in their effects. In the dose range tested, d-amphetamine significantly lowered the PTZ seizure threshold but increased the MEST, caffeine and theophylline did not alter the PTZ seizure threshold but decreased the MEST, and tramadol reduced the PTZ threshold but increased the MEST. These marked differences between seizure threshold tests are most likely a consequence of the mechanisms underlying seizure induction in these tests. Our data indicate that using only one seizure threshold model during preclinical drug development may pose the risk that potential proconvulsant activity of an investigational drug is overseen. However, the label "proconvulsant" may be misleading if such activity only occurs at doses high above the therapeutic range, but the drug is not proconvulsant or even exerts anticonvulsant effects at lower, therapeutically relevant doses.

Synthesis and in vivo evaluation of the putative breast cancer resistance protein inhibitor [11C]methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate.

INTRODUCTION: The multidrug efflux transporter breast cancer resistance protein (BCRP) is highly expressed in the blood-brain barrier (BBB), where it limits brain entry of a broad range of endogenous and exogenous substrates. Methyl is a recently discovered BCRP-selective inhibitor, which is structurally derived from the potent P-glycoprotein (P-gp) inhibitor tariquidar. The aim of this study was to develop a new PET tracer based on 1 to map BCRP expression levels in vivo. METHODS: Compound 1 was labelled with (11)C in its methyl ester function by reaction of the corresponding carboxylic acid 2 with [(11)C]methyl triflate. Positron emission tomography (PET) imaging of [(11)C]-1 was performed in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3 per mouse type) and radiotracer metabolism was assessed in plasma and brain. RESULTS: Brain-to-plasma ratios of unchanged [(11)C]-1 were 4.8- and 10.3-fold higher in Mdr1a/b((-/-)) and in Mdr1a/b((-/-))Bcrp1((-/-)) mice, respectively, as compared to wild-type animals, but only modestly increased in Bcrp1((-/-)) mice. [(11)C]-1 was rapidly metabolized in vivo giving rise to a polar radiometabolite which was taken up into brain tissue. CONCLUSION: Our data suggest that [(11)C]-1 preferably interacts with P-gp rather than BCRP at the murine BBB which questions its reported in vitro BCRP selectivity. Consequently, [(11)C]-1 appears to be unsuitable as a PET tracer to map cerebral BCRP expression.