TY  - JOUR
A1  - Grotemeyer, Alexander
A1  - Fischer, Judith F.
A1  - Koprich, James B.
A1  - Brotchie, Jonathan M.
A1  - Blum, Robert
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
T1  - Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease
JF  - Journal of Neuroinflammation
N2  - Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.
KW  - neurodegeneration
KW  - movement disorder
KW  - neuroinflammation
KW  - Parkinson’s disease
KW  - inflammasome
KW  - dopaminergic cells
KW  - NLRP3
KW  - MCC950
KW  - microglia
KW  - T cells
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357652
VL  - 20
ER  - 
TY  - JOUR
A1  - Bellut, Maximilian
A1  - Raimondi, Anthony T.
A1  - Haarmann, Axel
A1  - Zimmermann, Lena
A1  - Stoll, Guido
A1  - Schuhmann, Michael K.
T1  - NLRP3 inhibition reduces rt-PA induced endothelial dysfunction under ischemic conditions
JF  - Biomedicines
N2  - Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index — a sensible indicator for a patent BBB — and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke.
KW  - NLRP3
KW  - inflammasome
KW  - MCC950
KW  - rt-PA
KW  - blood–brain barrier
KW  - Cell Index
KW  - ASC
KW  - ischemic stroke
KW  - i.v. thrombolysis
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267261
SN  - 2227-9059
VL  - 10
IS  - 4
ER  -