R Hanstein

Publications (2)6.76 Total impact

• Article: Transgenic overexpression of corticotropin releasing hormone provides partial protection against neurodegeneration in an in vivo model of acute excitotoxic stress.

  R Hanstein, A Lu, W Wurst, F Holsboer, J M Deussing, A B Clement, C Behl
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  ABSTRACT: Corticotropin releasing hormone (CRH) is the central modulator of the mammalian hypothalamic-pituitary-adrenal (HPA) axis. In addition, CRH affects other processes in the brain including learning, memory, and synaptic plasticity. Moreover, CRH has been shown to play a role in nerve cell survival under apoptotic conditions and to serve as an endogenous neuroprotectant in vitro. Employing mice overexpressing murine CRH in the CNS, we observed a differential response of CRH-overexpressing mice (CRH-COEhom-Nes) to acute excitotoxic stress induced by kainate compared with controls (CRH-COEcon-Nes). Interestingly, CRH-overexpression reduced the duration of epileptic seizures and prevented kainate-induced neurodegeneration and neuroinflammation in the hippocampus. Our findings highlight a neuroprotective action of CRH in vivo. This neuroprotective effect was accompanied by increased levels of brain-derived neurotrophic factor (BDNF) in CRH-COEhom-Nes mice, suggesting a potential role for BDNF in mediating CRH-induced neuroprotective actions against acute excitotoxicity in vivo.
  Neuroscience 08/2008; 156(3):712-21. · 3.38 Impact Factor
• Article: Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress.

  A B Clement, R Hanstein, A Schröder, H Nagel, K Endres, F Fahrenholz, C Behl
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  ABSTRACT: A disintegrin and metalloprotease (ADAM) 10 is the main candidate enzyme for the alpha-secretase processing of the amyloid precursor protein (APP). Neuron-specific ADAM10 overexpression proved beneficial in the APP[V717I] mutant Alzheimer mouse model [Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456-1464]. Since Alzheimer patients have a high prevalence for epileptic seizures, we investigated the effects of ADAM10 modulation under conditions of experimentally induced epileptic seizures. In this context we also examined whether ADAM10 effects were influenced by APP levels. Therefore we compared severity of kainate-induced seizures, neurodegeneration and inflammation in double transgenic mice overexpressing functional ADAM10 or a dominant negative ADAM10 mutant in the APP[V717I] background with single transgenic ADAM10 modulated mice. Double transgenic dominant negative ADAM10dn/APP[V717I] mice suffered from stronger epileptic seizures, had a longer recovery period and showed more neurodegeneration and glial activation in the hippocampal region than double transgenic mice moderately overexpressing functional ADAM10 (ADAM10mo/APP[V717I]) and APP[V717I] mice with endogenous ADAM10 levels. This suggests that ADAM10 activity is necessary to provide neuroprotection against excitotoxicity in the APP[V717I] mouse model. Interestingly, increased expression of functional ADAM10 above the endogenous level did not correlate with a better protection against seizures and neurodegeneration. Furthermore, ADAM10 dominant negative mice without transgenic APP overexpression (ADAM10dn) were seizing for a shorter time and showed less neuronal cell death and neuroinflammation after kainate injection than wild-type mice, which shows beneficial effects of ADAM10 inhibition in context with neurodegeneration. In contrast, mice with a high ADAM10 overexpression showed more seizures and stronger neuronal damage and inflammation than wild-type mice and mice with moderate ADAM10 overexpression. Hence, additional cleavage products of ADAM10 may counterbalance the neuroprotective effect of alpha-secretase-cleaved APP in the defense against excitotoxicity. Our findings highlight the need of a careful modulation of ADAM10 activity for neuroprotection depending on substrate availability and on neurotoxic stress conditions.
  Neuroscience 04/2008; 152(2):459-68. · 3.38 Impact Factor