Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice

by Selleckchem | Jun 30 2023

Background: Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke.

Methods: Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO.

Results: Infarct sizes on day 7 after tMCAO decreased about 35% after delayed and about 60% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis.

Conclusions: Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome-even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke.

Comments:

The provided background describes a study that investigated the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Ischemic stroke refers to a condition where there is a lack of blood flow to a specific region of the brain due to a blockage in a blood vessel. This leads to immediate neuro-inflammatory responses and contributes to the development of the primary infarct (tissue damage) during vessel occlusion. Even after recanalization (restoration of blood flow), further infarct growth can occur due to ischemia/reperfusion injury.

The study used a mouse model of focal cerebral ischemia, where a transient middle cerebral artery occlusion (tMCAO) was induced for 30 minutes. The NLRP3 inhibitor MCC950 was administered either therapeutically 24 hours after tMCAO or prophylactically before tMCAO. The researchers then assessed stroke outcomes, including infarct size and functional deficits, as well as the local inflammatory response on day 7 after tMCAO.

The results showed that inhibiting NLRP3 had a significant effect on the outcome of the stroke. Compared to the control group, the infarct sizes on day 7 after tMCAO were reduced by approximately 35% when NLRP3 inhibition was delayed and by about 60% when it was administered prophylactically. Functionally, NLRP3 inhibition also mitigated the local inflammatory response in the ischemic brain, as evidenced by a reduction in infiltrating immune cells and reactive astrogliosis (activation of astrocytes, a type of glial cell).

In conclusion, the study demonstrates that the NLRP3 inflammasome continues to drive neuroinflammation during the subacute phase of ischemic stroke. Inhibiting NLRP3 has a positive impact on long-term outcomes, even when administered with a delay of 1 day after stroke induction. This suggests that ongoing inflammation plays a role in infarct progression and highlights the potential of targeting NLRP3 as a therapeutic strategy for ischemic stroke, including delayed treatment options.