Progesterone and Vitamin D Combination Therapy Modulates Inflammatory Response After Traumatic Brain Injury

Overview

Journal Brain Inj

Publisher Informa Healthcare

Specialty Neurology

Date 2015 Jun 18

PMID 26083048

Citations 25

Authors

Huiling Tang

Fang Hua

Jun Wang

Seema Yousuf

Fahim Atif

Iqbal Sayeed

Donald G Stein

Affiliations

Soon will be listed here.

Abstract

Objective: Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI) and may do so through Toll-like receptor (TLR)-mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway. This study tested the hypothesis that PROG and VDH would exert additive and synergistic neuroprotective effects compared with individual treatment by modulating TLR4/NF-κB-mediated inflammation pathways after TBI in rats.

Research Design And Methods: Bilateral medial frontal cortical impact injury was induced in young adult Sprague-Dawley rats. Progesterone (i.p., 16 mg kg body weight) and VDH (1 µg kg body weight) were injected separately or combined at 1 and 6 hours after surgery. Rats were killed 24 hours post-surgery and peri-contusional brain tissue harvested for immunostaining and protein measurement.

Results: TLR4, phosphorylation of NF-κB, neuronal loss and astrocyte activation were significantly reduced with combination treatment after TBI compared to each agent given individually.

Conclusions: At 24 hours after TBI, combination therapy shows greater efficacy in reducing neuroinflammation compared to progesterone and VDH given separately, and does so by modulating the TLR4/NF-κB signalling pathway.

Citing Articles

Vitamin D in Central Nervous System: Implications for Neurological Disorders.

Sailike B, Onzhanova Z, Akbay B, Tokay T, Molnar F Int J Mol Sci. 2024; 25(14).

PMID: 39063051 PMC: 11277055. DOI: 10.3390/ijms25147809.

Thiamine use is associated with better outcomes for traumatic brain injury patients.

Wang R, Zeng Y, Xu J, He M Front Nutr. 2024; 11:1362817.

PMID: 39036489 PMC: 11257909. DOI: 10.3389/fnut.2024.1362817.

An updated systematic review of neuroprotective agents in the treatment of spinal cord injury.

Serag I, Abouzid M, Elmoghazy A, Sarhan K, Alsaad S, Mohamed R Neurosurg Rev. 2024; 47(1):132.

PMID: 38546884 DOI: 10.1007/s10143-024-02372-6.

Pattern-recognition receptors in endometriosis: A narrative review.

Guo B, Chen J, Zhang J, Fang Y, Liu X, Zhang J Front Immunol. 2023; 14:1161606.

PMID: 37033937 PMC: 10076794. DOI: 10.3389/fimmu.2023.1161606.

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review.

Lynch D, Narayan R, Li C J Clin Med. 2023; 12(6).

PMID: 36983181 PMC: 10052098. DOI: 10.3390/jcm12062179.

References

Sinz E, Kochanek P, Dixon C, Clark R, Carcillo J, Schiding J . Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. J Clin Invest. 1999; 104(5):647-56. PMC: 408535. DOI: 10.1172/JCI6670. View

Pahl H . Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999; 18(49):6853-66. DOI: 10.1038/sj.onc.1203239. View

Strauss K, Barbe M, Marshall R, Raghupathi R, Mehta S, Narayan R . Prolonged cyclooxygenase-2 induction in neurons and glia following traumatic brain injury in the rat. J Neurotrauma. 2000; 17(8):695-711. PMC: 1456323. DOI: 10.1089/089771500415436. View

Surh Y, Chun K, Cha H, Han S, Keum Y, Park K . Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 2001; 480-481:243-68. DOI: 10.1016/s0027-5107(01)00183-x. View

Morganti-Kossmann M, Rancan M, Stahel P, Kossmann T . Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care. 2002; 8(2):101-5. DOI: 10.1097/00075198-200204000-00002. View

Karin M, Yamamoto Y, Wang Q . The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 2004; 3(1):17-26. DOI: 10.1038/nrd1279. View

Takeda K, Akira S . TLR signaling pathways. Semin Immunol. 2004; 16(1):3-9. DOI: 10.1016/j.smim.2003.10.003. View

Grossman K, Goss C, Stein D . Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 2004; 1008(1):29-39. DOI: 10.1016/j.brainres.2004.02.022. View

Yamamoto Y, Gaynor R . IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004; 29(2):72-9. DOI: 10.1016/j.tibs.2003.12.003. View

10.

Pettus E, Wright D, Stein D, Hoffman S . Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005; 1049(1):112-9. DOI: 10.1016/j.brainres.2005.05.004. View

11.

Myer D, Gurkoff G, Lee S, Hovda D, Sofroniew M . Essential protective roles of reactive astrocytes in traumatic brain injury. Brain. 2006; 129(Pt 10):2761-72. DOI: 10.1093/brain/awl165. View

12.

Cafferty W, Yang S, Duffy P, Li S, Strittmatter S . Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans. J Neurosci. 2007; 27(9):2176-85. PMC: 2848955. DOI: 10.1523/JNEUROSCI.5176-06.2007. View

13.

Caso J, Pradillo J, Hurtado O, Lorenzo P, Moro M, Lizasoain I . Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 2007; 115(12):1599-608. DOI: 10.1161/CIRCULATIONAHA.106.603431. View

14.

Hua F, Ma J, Ha T, Xia Y, Kelley J, Williams D . Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J Neuroimmunol. 2007; 190(1-2):101-11. PMC: 2453597. DOI: 10.1016/j.jneuroim.2007.08.014. View

15.

Cutler S, Cekic M, Miller D, Wali B, Vanlandingham J, Stein D . Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma. 2007; 24(9):1475-86. DOI: 10.1089/neu.2007.0294. View

16.

Huttemann M, Lee I, Kreipke C, Petrov T . Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels. Neuroscience. 2007; 151(1):148-54. DOI: 10.1016/j.neuroscience.2007.09.029. View

17.

Chen G, Shi J, Jin W, Wang L, Xie W, Sun J . Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci. 2008; 38(1):65-74. View

18.

Foley L, Hitchens T, Melick J, Bayir H, Ho C, Kochanek P . Effect of inducible nitric oxide synthase on cerebral blood flow after experimental traumatic brain injury in mice. J Neurotrauma. 2008; 25(4):299-310. DOI: 10.1089/neu.2007.0471. View

19.

Gilmer L, Roberts K, Scheff S . Efficacy of progesterone following a moderate unilateral cortical contusion injury. J Neurotrauma. 2008; 25(6):593-602. PMC: 2946876. DOI: 10.1089/neu.2007.0477. View

20.

Kenny E, ONeill L . Signalling adaptors used by Toll-like receptors: an update. Cytokine. 2008; 43(3):342-9. DOI: 10.1016/j.cyto.2008.07.010. View