Skip to main content

Advertisement

SpringerLink
Log in

VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation

  • RESEARCH
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50 mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30 days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The data are available from the corresponding author on reasonable request.

References

  • Ali AAH, Stahr A, Ingenwerth M, Theis M, Steinhuser C, Gall CV (2019) Connexin30 and Connexin43 show a time-of-day dependent expression in the mouse suprachiasmatic nucleus and modulate rhythmic locomotor activity in the context of chronodisruption. Cell Commun Signal: CCS 17

  • Armstrong RC, Mierzwa AJ, Marion CM, Sullivan GM (2016) White matter involvement after TBI: clues to axon and myelin repair capacity. Exp Neurol 275(Pt 3):328–333

    Article  CAS  PubMed  Google Scholar 

  • Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Büchele F, Morawska MM, Schreglmann SR, Penner M, Muser M, Baumann CR et al (2016) Novel rat model of weight drop-induced closed diffuse traumatic brain injury compatible with electrophysiological recordings of vigilance states. J Neurotrauma 33:1171–1180

    Article  PubMed  Google Scholar 

  • Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Challet E, Poirel VJ, Malan A, Pévet P (2003) Light exposure during daytime modulates expression of Per1 and Per2 clock genes in the suprachiasmatic nuclei of mice. J Neurosci Res 72:629–637

    Article  CAS  PubMed  Google Scholar 

  • Crunelli V, Blethyn KL, Cope DW, Hughes SW, Parri HR, Turner JP et al (2002) Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics. Philos Trans R Soc Lond B Biol Sci 357:1675–1693

    Article  PubMed  PubMed Central  Google Scholar 

  • Demers M, Suidan GL, Andrews N, Martinod K, Cabral JE, Wagner DD (2018) Solid peripheral tumor leads to systemic inflammation, astrocyte activation and signs of behavioral despair in mice. PLoS One 13:e0207241

    Article  PubMed  PubMed Central  Google Scholar 

  • Eroglu O, Deniz T, Kisa U, Atasoy P, Aydinuraz K (2017) Effect of hypothermia on apoptosis in traumatic brain injury and hemorrhagic shock model. Injury 48:2675–2682

    Article  PubMed  Google Scholar 

  • Ertmer C, Kampmeier T, Rehberg S, Lange M (2011) Fluid resuscitation in multiple trauma patients. Curr Opin Anaesthesiol 24:202–208

    Article  PubMed  Google Scholar 

  • Fahrenkrug J, Georg B, Hannibal J, Jørgensen HL (2017) Hypophysectomy abolishes rhythms in rat thyroid hormones but not in the thyroid clock. J Endocrinol 233:209–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flores J, Noel A, Foveau B, Lynham J, Lecrux C, LeBlanc AC (2018) Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat Commun 9:3916

    Article  PubMed  PubMed Central  Google Scholar 

  • Gilbert KS, Kark SM, Gehrman P, Bogdanova Y (2015) Sleep disturbances, TBI and PTSD: implications for treatment and recovery. Clin Psychol Rev 40:195–212

    Article  PubMed  PubMed Central  Google Scholar 

  • Gormley S, Rouine J, McIntosh A et al (2016) Glial fibrillary acidic protein (GFAP) immunoreactivity correlates with cortical perfusion parameters determined by bolus tracking arterial spin labelling (bt-ASL) magnetic resonance (MR) imaging in the Wistar Kyoto rat. Physiol Behav

  • Hamblin MR (2018) Photobiomodulation for traumatic brain injury and stroke. J Neurosci Res 96:731–743

    Article  CAS  PubMed  Google Scholar 

  • Haruki H, Sano Y, Shimizu F, Omoto M, Tasaki A, Oishi M et al (2013) NMO sera down-regulate AQP4 in human astrocyte and induce cytotoxicity independent of complement. J Neurol Sci 331:136–144

    Article  CAS  PubMed  Google Scholar 

  • Haydon PG (2017) Astrocytes and the modulation of sleep. Curr Opin Neurobiol 44:28–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong Y, Liu Y, Yu D, Wang M, Hou Y (2019) The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes. Int Immunopharmacol 74:105669

    Article  CAS  PubMed  Google Scholar 

  • Houweling AR, Bazhenov M, Timofeev I, Steriade M, Sejnowski TJ (2005) Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex. Cereb Cortex (New York, N.Y.: 1991) 15:834–845

  • Imeri L, Bianchi S, Opp MR (2006) Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol 291:R197-204

    Article  CAS  PubMed  Google Scholar 

  • Jia YF, Vadnie CA, Ho AM, Peyton L, Veldic M, Wininger K et al (2020) Type 1 equilibrative nucleoside transporter (ENT1) regulates sex-specific ethanol drinking during disruption of circadian rhythms. Addict Biol 25:e12801

    Article  CAS  PubMed  Google Scholar 

  • Katz DI, Cohen SI, Alexander MP (2015) Mild traumatic brain injury. Handb Clin Neurol 127:131–156

    Article  PubMed  Google Scholar 

  • Larson EB (2018) Sleep disturbance and cognition in people with TBI. NeuroRehabilitation 43:297–306

    Article  PubMed  Google Scholar 

  • Leibowitz A, Brotfain E, Koyfman L, Klein M, Hess S, Zlotnik A et al (2019) Treatment of combined traumatic brain injury and hemorrhagic shock with fractionated blood products versus fresh whole blood in a rat model. Eur J Trauma Emerg Surg 45:263–271

    Article  PubMed  Google Scholar 

  • Li Y, Zhang LM, Zhang DX, Zheng WC, Bai Y, Bai J et al (2020) CORM-3 ameliorates neurodegeneration in the amygdala and improves depression- and anxiety-like behavior in a rat model of combined traumatic brain injury and hemorrhagic shock. Neurochem Int 140:104842

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Li Y, Cui Y, Roberts C, Lu M, Wilhelmsson U et al (2014) Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia 62:2022–2033

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu W, Chen Y, Meng J, Wu M, Bi F, Chang C et al (2018) Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo. J Neuroinflammation 15:48

    Article  PubMed  PubMed Central  Google Scholar 

  • Marmarou A, Foda MAA, Den Brink WV, Campbell J, Kita H, Demetriadou K (1994) A new model of diffuse brain injury in rats: part I: pathophysiology and biomechanics. J Neurosurg 80:291–300

    Article  CAS  PubMed  Google Scholar 

  • Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J et al (2011) Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8:304–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKee CA, Lee J, Cai Y, Saito T, Saido T, Musiek ES (2022) Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden. Sci Rep 12:1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKenzie BA, Mamik MK, Saito LB, Boghozian R, Monaco MC, Major EO et al (2018) Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci U S A 115:E6065–E6074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niogi SN, Mukherjee P, Ghajar J, Johnson C, Kolster RA, Sarkar R et al (2008) Extent of microstructural white matter injury in postconcussive syndrome correlates with impaired cognitive reaction time: a 3T diffusion tensor imaging study of mild traumatic brain injury. AJNR Am J Neuroradiol 29:967–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orff HJ, Ayalon L, Drummond SP (2009) Traumatic brain injury and sleep disturbance: a review of current research. J Head Trauma Rehabil 24:155–165

    Article  PubMed  Google Scholar 

  • Park MJ, Sohrabji F (2016) The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats. J Neuroinflammation 13:300

    Article  PubMed  PubMed Central  Google Scholar 

  • Poh L, Kang SW, Baik SH, Ng GYQ, She DT, Balaganapathy P et al (2019) Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain Behav Immun 75:34–47

    Article  CAS  PubMed  Google Scholar 

  • Radomski M, Zettervall S, Schroeder ME, Messing J, Dunne J, Sarani B (2016) Critical care for the patient with multiple trauma. J Intensive Care Med 31:307–318

    Article  PubMed  Google Scholar 

  • Rutgers DR, Toulgoat F, Cazejust J, Fillard P, Lasjaunias P, Ducreux D (2008) White matter abnormalities in mild traumatic brain injury: a diffusion tensor imaging study. AJNR Am J Neuroradiol 29:514–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandsmark DK, Elliott JE, Lim MM (2017) Sleep-wake disturbances after traumatic brain injury: synthesis of human and animal studies. Sleep  40

  • Savin C, Triesch J, Meyer-Hermann M (2009) Epileptogenesis due to glia-mediated synaptic scaling. J R Soc Interface 6:655–668

    Article  CAS  PubMed  Google Scholar 

  • Sen N (2017) An insight into the vision impairment following traumatic brain injury. Neurochem Int 111:103–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shekleton JA, Parcell DL, Redman JR, Phipps-Nelson J, Ponsford JL, Rajaratnam SM (2010) Sleep disturbance and melatonin levels following traumatic brain injury. Neurology 74:1732–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skopin MD, Kabadi SV, Viechweg SS, Mong JA, Faden AI (2015) Chronic decrease in wakefulness and disruption of sleep-wake behavior after experimental traumatic brain injury. J Neurotrauma 32:289–296

    Article  PubMed  PubMed Central  Google Scholar 

  • Song Z, Shen F, Zhang Z, Wu S, Zhu G (2020) Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus. Neuropharmacology 174:108175

    Article  CAS  PubMed  Google Scholar 

  • Spinedi E, Cardinali DP (2019) Neuroendocrine-metabolic dysfunction and sleep disturbances in neurodegenerative disorders: focus on alzheimer’s disease and melatonin. Neuroendocrinology 108:354–364

    Article  CAS  PubMed  Google Scholar 

  • Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E et al (2017) Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551:192–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugiyama M, Nishijima I, Miyazaki S, Nakamura TJ (2020) Secretin receptor-deficient mice exhibit altered circadian rhythm in wheel-running activity. Neurosci Lett 722:134814

    Article  CAS  PubMed  Google Scholar 

  • Thomasy HE, Febinger HY, Ringgold KM, Gemma C, Opp MR (2017) Hypocretinergic and cholinergic contributions to sleep-wake disturbances in a mouse model of traumatic brain injury. Neurobiol Sleep Circadian Rhythms 2:71–84

    Article  PubMed  Google Scholar 

  • Tu TW, Williams RA, Lescher JD, Jikaria N, Turtzo LC, Frank JA (2016) Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model. Ann Neurol 79:907–920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verwey M, Robinson B, Amir S (2013) Recording and analysis of circadian rhythms in running-wheel activity in rodents. J Vis Exp

  • Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB (2021) Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. Proc Natl Acad Sci USA 118

  • Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G et al (2007) (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 321:509–516

    Article  CAS  PubMed  Google Scholar 

  • Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z et al (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci : Off J Soc Neurosci 33:12870–12886

    Article  CAS  Google Scholar 

  • Xu XE, Liu L, Wang YC, Wang CT, Zheng Q, Liu QX et al (2019) Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis. Brain Behav Immun 80:859–870

    Article  CAS  PubMed  Google Scholar 

  • Yarossi M, Patel J, Qiu Q, Massood S, Fluet G, Merians A et al (2019) The association between reorganization of bilateral m1 topography and function in response to early intensive hand focused upper limb rehabilitation following stroke is dependent on ipsilesional corticospinal tract integrity. Front Neurol 10:258

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang LM, Zhang DX, Fu L, Li Y, Wang XP, Qi MM et al (2019) Carbon monoxide-releasing molecule-3 protects against cortical pyroptosis induced by hemorrhagic shock and resuscitation via mitochondrial regulation. Free Radic Biol Med 141:299–309

    Article  CAS  PubMed  Google Scholar 

  • Zhang DX, Zheng WC, Bai Y, Bai J, Fu L, Wang XP et al (2020) CORM-3 improves emotional changes induced by hemorrhagic shock via the inhibition of pyroptosis in the amygdala. Neurochem Int 139:104784

    Article  CAS  PubMed  Google Scholar 

  • Zhang LM, Zhang DX, Zheng WC, Hu JS, Fu L, Li Y et al (2021) CORM-3 exerts a neuroprotective effect in a rodent model of traumatic brain injury via the bidirectional gut-brain interactions. Exp Neurol 341:113683

    Article  CAS  PubMed  Google Scholar 

  • Zhang LM, Zhang DX (2019) The dual neuroprotective-neurotoxic effects of sevoflurane after hemorrhagic shock injury. J Surg Res 235:591–599

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Liu L, Liu YZ, Shen XL, Wu TY, Zhang T et al (2015) NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int J Neuropsychopharmacol 18

  • Zhou Y, Gu Y, Liu J (2019) BRD4 suppression alleviates cerebral ischemia-induced brain injury by blocking glial activation via the inhibition of inflammatory response and pyroptosis. Biochem Biophys Res Commun 519:481–488

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

National Natural Science Foundation of China, 81701296, Li-Min Zhang, 82171455, Li-Min Zhang, Natural Science Foundation of Hebei Province, H2021110004, Dong-Xue Zhang, Natural Science Foundation of Cangzhou, 221001011D, Li-Min Zhang.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China

    Yan Li & Man-Man Qi

  2. Department of Anesthesiology, Graduated School, Hebei Medical University, Cangzhou, China

    Yue Xin, Wei-Chao Zheng & Jie-Xia Wang

  3. Department of Neurosurgery, Graduated School, Hebei Medical University, Cangzhou, China

    Zhi-You Wu

  4. Department of Anesthesiology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine (Cangzhou No.2 Hospital), Cangzhou, China

    Han Wang & Li-Min Zhang

  5. Department of Gerontology, Cangzhou Central Hospital, Cangzhou, China

    Dong-Xue Zhang

  6. Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China

    Li-Min Zhang

  7. Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Cangzhou, China

    Li-Min Zhang

Authors
  1. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Man-Man Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-You Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Chao Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jie-Xia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dong-Xue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Li-Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design of the study: Li-Min Zhang, Yan Li Editing the manuscript: Li-Min Zhang, Yan Li Statistical analysis: Li-Min Zhang, Dong-Xue Zhang Experiment and data collection: Yan Li, Yue Xin, Jie-Xia Wang, Wei-Chao Zheng, Man-Man Qi, Han Wang, Zhi-You Wu All authors read and approved the final manuscript.

Corresponding author

Correspondence to Li-Min Zhang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Xin, Y., Qi, MM. et al. VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation. J Neuroimmune Pharmacol 19, 3 (2024). https://doi.org/10.1007/s11481-024-10102-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11481-024-10102-4

Keywords

Search

Navigation