Telmisartan reduced cerebral edema by inhibiting NLRP3 inflammasome in mice with cold brain injury

Abstract

The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury (TBI) and the potential mechanisms related to the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier (BBB) integrity, the neurological function and histological injury were assessed, at the same time, the mRNA and protein expression levels of NLRP3 inflammasome, IL-1β and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein (ASC) and Caspase-1 activation, as well as IL-1β and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1β and IL-18 accumulation.

Lack of the Nlrp3 Inflammasome Improves Mice Recovery Following Traumatic Brain Injury

“…The few papers, so far published on the role of NLRP3 in TBI used indirect strategies to prevent NLRP3 activation (Liu et al, 2013; Dong et al, 2016; Ma et al, 2016; Wei et al, 2016; Lin et al, 2017). A study using telmisartan in mice subjected to cold brain injury showed that the treatment reduced oxidative stress and brain oedema, as a consequence NLRP3 and IL-1b production were decreased; however, the effect on this pathway is rather indirect than direct (Wei et al, 2016).…”

“…A study using telmisartan in mice subjected to cold brain injury showed that the treatment reduced oxidative stress and brain oedema, as a consequence NLRP3 and IL-1b production were decreased; however, the effect on this pathway is rather indirect than direct (Wei et al, 2016). …”

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…In addition, a number of recent studies have found that pharmacological treatments that directly or indirectly target this inflammasome can reduce its activity following moderate-to-severe TBI. These treatments are broadly broken into four groups: (i) treatments derived from naturally occurring compounds (e.g., mangiferin [83], omega-3 fatty acids [71], and apocynin [84]); (ii) repurposed medications (e.g., propofol [85], and telmisartan [86]); (iii) inhibitors of NLRP3-associated molecules (e.g., ASC antibodies [87], NF-κB inhibitor, Bay 11-7082 [88][89][90][91]); and (iv) specific NLRP3 inflammasome inhibitors (e.g., MCC950 [69], JC-124 [92]). While the first three treatment categories have been shown to decrease NLRP3 inflammasome activity as well as demonstrating a neuroprotective effect, they do not target NLRP3 activation specifically.…”

MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury

“…Neurobehavioral assessment was performed at 24 and 72 h post-TBI in a blinded fashion using a 10-point neurological severity score (NSS). 18 One point was given for each failure to account for the cumulative score with a maximum of 10. The assessment consisted of 10 different tasks: 1) presence of mono-or hemiparesis; 2) inability to walk on a 3-cm-wide beam; 3) inability to walk on a 2-cm-wide beam; 4) inability to walk on a 1-cm-wide beam; 5) inability to balance on a 1-cm-wide beam; 6) inability to balance on a round stick (0.5 cm diameter); 7) failure to exit a 30-cm-diameter circle (for 2 min); 8) inability to walk a straight line; 9) loss of startle behavior; and 10) loss of seeking behavior.…”

“…Applying general neuroprotectives like omega-3 fatty acids or telmisartan in experimental TBI, there are some earlier studies to suggest the association with NLRP3 inhibition may account for the therapeutic effects. 16,18,19 Nevertheless, generally acting as antioxidants or peleiotropic agents, the implication of a wide array of effectors may not be ruled out for such multipotential compounds. 20,21 Based on such a background, we used the newly developed NLRP3 inhibitor, MCC950, as a highly selective and potent inhibitor, to specify the involvement of NLRP3.…”