Necrosulfonamide Alleviates Acute Brain Injury of Intracerebral Hemorrhage via Inhibiting Inflammation and Necroptosis

Abstract

ObjectiveIntracerebral hemorrhage (ICH) is the most lethal subtype of stroke, without effective treatment. Necrosulfonamide (NSA), a specific inhibitor for mixed lineage kinase domain-like protein, has been reported to exert neuroprotective effects in neurological diseases by ameliorating neuroinflammation and necroptosis. We hypothesized that NSA would alleviate acute brain injury and improve behavioral outcomes after ICH.Materials and MethodsMale adult C57BL/6 mice were assigned randomly into three groups. In vehicle and treatment groups, animals were injected with collagenase VII to induce ICH. The solvent (0.25% DMSO) and NSA (5 mg/kg) were administrated intraperitoneally twice a day, respectively. The sham group was injected with saline and administrated with DMSO. The brain hematoma volume, inflammatory factors, and blood-brain barrier permeability were measured on day 3 after the operation. Fluorescent double immunostaining was performed to evaluate the neuronal death. Neurological functions were assessed.ResultsIn the NSA group, the hematoma size was significantly reduced, inflammatory cells and cytokines were suppressed, and the blood-brain barrier was protected compared to vehicle controls. NSA dramatically reduced the death of neurons and improved the performance of neurological functions after ICH.ConclusionNecrosulfonamide has a neuroprotective role in alleviating acute brain injury in a mouse ICH model, and this is associated with reduced neuroinflammation and necroptosis.

Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and α-synuclein oligomerization in a subacute MPTP mouse model of Parkinson’s disease

“…This study revealed more pMLKL + /TH + and pMLKL + /Ub + cells measured through histological data, and higher ubiquitylated pMLKL levels measured using co-immunoprecipitation assay in MPTP-intoxicated SN than in the control group, and the reversal effects of NSA exposure implied that repeated treatment with NSA hinders the cell death-inducing activity of MLKL in PD mice. Furthermore, our finding that NSA had no effect on the MPTP-induced increase in RIPK1 and RIPK3 protein levels corresponded to previous findings in rodent models 4 , 31 , indicating that NSA acts specifically on MLKL in vivo. NSA treatment reduced the MPTP-induced increase in MLKL protein levels in the MPTP mice.…”

“…Furthermore, NSA exhibited neuroprotective effects after ischemic brain injury in mice by inducing MLKL ubiquitination and degradation 32 . Moreover, NSA alleviated acute brain injury in a mouse intracerebral hemorrhage model by inhibiting inflammation and necroptosis 4 . However, the potential effect of NSA on the pathophysiology of PD has not yet been reported.…”

“…Necroptosis is a type of programmed cell death implicated in various pathological conditions, including infection, inflammation, ischemic injury, spinal cord injury, and neurodegeneration 1 – 4 . Necroptosis is indicated by plasma membrane disruption and leakage of damage-associated molecular patterns (DAMPs), such as the high mobility group box 1 protein and mitochondrial DNA, which can lead to a robust immune response and inflammation 5 – 7 .…”

The regulation of self-tolerance and the role of inflammasome molecules

“…However, testing of the related caspase-1 inhibitor VX-740 was discontinued in a RA clinical trial due to the liver toxicity observed in animal models ( 295 ). Inhibiting GSDMD by necrosulfonamide reduces neuroinflammation and necroptosis in collagenase VII-induced mouse intracerebral hemorrhage model ( 277 ). In addition, dimethyl fumarate, an immunosuppressive drug used for the treatment of recurrent remission MS and plaque psoriasis promotes succination of GSDMD, which in turn disrupts the interaction with caspase-1 and blocks pyropotosis ( 278 ).…”

Application of nanomaterials in the treatment of intracerebral hemorrhage

“…1 Neuroinflammation and oxidative stress are involved in secondary brain injury after ICH, [2][3][4] and the extensive literature on these pathogenic mechanisms uncover new insights to counter the pathologic sequelae of ICH. At present, surgical or traditional treatments are still the main options, 5,6 broad pre-clinical studies have been completed, [7][8][9] and numerous researches are pouring in, [10][11][12] however, there is no widely recognized and effective method to ameliorate secondary brain injury 13 and improve the prognosis of ICH. 14 For example, applying hyperosmolar agents and external ventricular drain placement to cope with the decreased alertness caused by mass effect of ICH may be appropriate.…”