TY  - JOUR
A1  - Minnerup, Jens
A1  - Sutherland, Brad A.
A1  - Buchan, Alastair M.
A1  - Kleinschnitz, Christoph
T1  - Neuroprotection for Stroke: Current Status and Future Perspectives
JF  - International Journal of Molecular Science
N2  - Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.
KW  - free radical scavenger
KW  - ischemic cascade
KW  - acute ischemic stroke
KW  - trial
KW  - focal cerebral-ischemia
KW  - interleukin-1 receptor antagonist
KW  - colony-stimulating factor
KW  - tissue-plasminogen activator
KW  - traumatic brain injury
KW  - placebo-controlled
KW  - alias pilot trial
KW  - damage cool aid
KW  - neuroprotection
KW  - ischemic stroke
KW  - translation
KW  - STAIR
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134730
VL  - 13
IS  - 9
ER  - 
TY  - JOUR
A1  - Michalski, D.
A1  - Heindl, M.
A1  - Kacza, J.
A1  - Laignel, F.
A1  - Küppers-Tiedt, L.
A1  - Schneider, D.
A1  - Grosche, J.
A1  - Boltze, J.
A1  - Löhr, M.
A1  - Hobohm, C.
A1  - Härtig, W.
T1  - Spatio-temporal course of macrophage-like cell accumulation after experimental embolic stroke depending on treatment with tissue plasminogen activator and its combination with hyperbaric oxygenation
JF  - European Journal of Histochemistry
N2  - Inflammation following ischaemic stroke attracts high priority in current research, particularly using human-like models and long-term observation periods considering translational aspects. The present study aimed on the spatio-temporal course of macrophage-like cell accumulation after experimental thromboembolic stroke and addressed microglial and astroglial reactions in the ischaemic border zone. Further, effects of tissue plasminogen activator (tPA) as currently best treatment for stroke and the potentially neuroprotective co-administration of hyperbaric oxygen (HBO) were investigated. Rats underwent middle cerebral artery occlusion and were assigned to control, tPA or tPA+HBO. Twenty-four hours, 7, 14 and 28 days were determined as observation time points. The accumulation of macrophage-like cells was semiquantitatively assessed by CD68 staining in the ischaemic area and ischaemic border zone, and linked to the clinical course. CD11b, ionized calcium binding adaptor molecule 1 (Iba), glial fibrillary acidic protein (GFAP) and Neuronal Nuclei (NeuN) were applied to reveal delayed glial and neuronal alterations. In all groups, the accumulation of macrophage-like cells increased distinctly from 24 hours to 7 days post ischaemia. tPA+HBO tended to decrease macrophage-like cell accumulation at day 14 and 28. Overall, a trend towards an association of increased accumulation and pronounced reduction of the neurological deficit was found. Concerning delayed inflammatory reactions, an activation of microglia and astrocytes with co-occurring neuronal loss was observed on day 28. Thereby, astrogliosis was found circularly in contrast to microglial activation directly in the ischaemic area. This study supports previous data on long-lasting inflammatory processes following experimental stroke, and additionally provides region-specific details on glial reactions. The tendency towards a decreasing macrophage-like cell accumulation after tPA+HBO needs to be discussed critically since neuroprotective properties were recently ascribed to long-term inflammatory processes.
KW  - blood-brain-barrier
KW  - focal cerebral-ischemia
KW  - experimental stroke
KW  - macrophages
KW  - HBO
KW  - tPA
KW  - tumor-necrosis-factor
KW  - inflammatory mechanisms
KW  - mononuclear phagocytes
KW  - astroglia
KW  - microglia
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133136
VL  - 56
IS  - 2
SP  - 78
EP  - 89
ER  -