Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways

Yao,Chengye; Zhang,Jiancheng; Chen,Fang; Lin,Yun

doi:10.3892/mmr.2013.1543

Neuroprotectin D1 attenuates brain damage induced by transient middle cerebral artery occlusion in rats through TRPC6/CREB pathways

Authors:
- Chengye Yao
- Jiancheng Zhang
- Fang Chen
- Yun Lin
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Affiliations: Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: June 25, 2013 https://doi.org/10.3892/mmr.2013.1543
Pages: 543-550

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Abstract

Neuroprotectin D1 (NPD1) may serve an endogenous neuroprotective role in brain ischemic injury, yet the underlying mechanism involved is poorly understood. In the present study, we aimed to investigate whether intracerebroventricular (ICV) injection of NPD1 is neuroprotective against transient focal cerebral ischemia. We also sought to verify the neuroprotective mechanisms of NPD1. Rats subjected to 2 h ischemia followed by reperfusion were treated with NPD1 at 2 h after reperfusion. PD98059 was administered 20 min prior to surgery. Western blot analysis was performed to detect the protein levels of calpain-specific aII-spectrin breakdown products of 145 kDa (SBDP145), transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylation of cAMP/Ca2+-response element binding protein (p-CREB) at 12, 24 and 48 h after reperfusion. The immunoreactivity of p-CREB and TRPC6 was measured by quantum dot‑based immunofluorescence analysis. Infarct volume and neurological scoring were evaluated at 48 h after reperfusion. NPD1, when applied at 2 h after reperfusion, significantly reduced infarct volumes and increased neurological scores at 48 h after reperfusion, accompanied by elevated TRPC6 and p-CREB activity, and decreased SBDP145 activity. When mitogen‑activated protein kinase kinase (MEK) activity was specifically inhibited, the neuroprotective effect of NPD1 was attenuated and correlated with decreased CREB activity. Our results clearly showed that ICV injection of NPD1 at 2 h after reperfusion improves the neurological status of middle cerebral artery occlusion (MCAO) rats through the inhibition of calpain‑mediated TRPC6 proteolysis and the subsequent activation of CREB via the Ras/MEK/ERK pathway.

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1	Dirnagl U, Iadecola C and Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22:391–397. 1999. View Article : Google Scholar : PubMed/NCBI
2	Lo EH, Dalkara T and Moskowitz MA: Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 4:399–415. 2003. View Article : Google Scholar : PubMed/NCBI
3	Lo EH: A new penumbra: transitioning from injury into repair after stroke. Nat Med. 14:497–500. 2008. View Article : Google Scholar : PubMed/NCBI
4	Choi DW: Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol. 6:667–672. 1996. View Article : Google Scholar
5	Lipton P: Ischemic cell death in brain neurons. Physiol Rev. 79:1431–1568. 1999.PubMed/NCBI
6	Bartus RT, Dean RL, Cavanaugh K, Eveleth D, Carriero DL and Lynch G: Time-related neuronal changes following middle cerebral artery occlusion: implications for therapeutic intervention and the role of calpain. J Cereb Blood Flow Metab. 15:969–979. 1995. View Article : Google Scholar
7	Lipton SA and Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 330:613–622. 1994. View Article : Google Scholar : PubMed/NCBI
8	Du W, Huang J, Yao H, Zhou K, Duan B and Wang Y: Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats. J Clin Invest. 120:3480–3492. 2010. View Article : Google Scholar : PubMed/NCBI
9	Jia Y, Zhou J, Tai Y and Wang Y: TRPC channels promote cerebellar granule neuron survival. Nat Neurosci. 10:559–567. 2007. View Article : Google Scholar : PubMed/NCBI
10	Simopoulos AP: Omega-3 fatty acids, the brain and retina. Preface. World Rev Nutr Diet. 99:VII–XII. 2009.PubMed/NCBI
11	Niemoller TD, Stark DT and Bazan NG: Omega-3 fatty acid docosahexaenoic acid is the precursor of neuroprotectin D1 in the nervous system. World Rev Nutr Diet. 99:46–54. 2009. View Article : Google Scholar : PubMed/NCBI
12	Marcheselli VL, Hong S, Lukiw WJ, et al: Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem. 278:43807–43817. 2003. View Article : Google Scholar
13	Bazan NG: Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci. 29:263–271. 2006. View Article : Google Scholar : PubMed/NCBI
14	Belayev L, Marcheselli VL, Khoutorova L, et al: Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke. 36:118–123. 2005. View Article : Google Scholar : PubMed/NCBI
15	Rodriguez DTE, Belayev L, Liu Y, et al: Systemic fatty acid responses to transient focal cerebral ischemia: influence of neuroprotectant therapy with human albumin. J Neurochem. 83:515–524. 2002. View Article : Google Scholar : PubMed/NCBI
16	Bazan NG: Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture. Invest Ophthalmol Vis Sci. 48:4866–4881. 4864–4865. 2007. View Article : Google Scholar : PubMed/NCBI
17	Tsubokawa T, Jadhav V, Solaroglu I, Shiokawa Y, Konishi Y and Zhang JH: Lecithinized superoxide dismutase improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. Stroke. 38:1057–1062. 2007. View Article : Google Scholar : PubMed/NCBI
18	Shen H, Chen GJ, Harvey BK, Bickford PC and Wang Y: Inosine reduces ischemic brain injury in rats. Stroke. 36:654–659. 2005. View Article : Google Scholar : PubMed/NCBI
19	Shen H, Kuo CC, Chou J, et al: Astaxanthin reduces ischemic brain injury in adult rats. Faseb J. 23:1958–1968. 2009. View Article : Google Scholar : PubMed/NCBI
20	Hardingham GE, Fukunaga Y and Bading H: Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 5:405–414. 2002.PubMed/NCBI
21	Goll DE, Thompson VF, Li H, Wei W and Cong J: The calpain system. Physiol Rev. 83:731–801. 2003. View Article : Google Scholar
22	Yao H, Ginsberg MD, Eveleth DD, et al: Local cerebral glucose utilization and cytoskeletal proteolysis as indices of evolving focal ischemic injury in core and penumbra. J Cereb Blood Flow Metab. 15:398–408. 1995. View Article : Google Scholar : PubMed/NCBI
23	Hong SC, Goto Y, Lanzino G, Soleau S, Kassell NF and Lee KS: Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke. 25:663–669. 1994. View Article : Google Scholar : PubMed/NCBI
24	Roberts-Lewis JM, Savage MJ, Marcy VR, Pinsker LR and Siman R: Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain. J Neurosci. 14:3934–3944. 1994.PubMed/NCBI
25	von Reyn CR, Spaethling JM, Mesfin MN, et al: Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit. J Neurosci. 29:10350–10356. 2009.
26	Montell C, Jones K, Hafen E and Rubin G: Rescue of the Drosophila phototransduction mutation trp by germline transformation. Science. 230:1040–1043. 1985. View Article : Google Scholar : PubMed/NCBI
27	Harteneck C, Plant TD and Schultz G: From worm to man: three subfamilies of TRP channels. Trends Neurosci. 23:159–166. 2000. View Article : Google Scholar : PubMed/NCBI
28	Montell C, Birnbaumer L and Flockerzi V: The TRP channels, a remarkably functional family. Cell. 108:595–598. 2002. View Article : Google Scholar : PubMed/NCBI
29	Li Y, Jia YC, Cui K, et al: Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature. 434:894–898. 2005. View Article : Google Scholar : PubMed/NCBI
30	Tai Y, Feng S, Ge R, et al: TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. J Cell Sci. 121:2301–2307. 2008. View Article : Google Scholar : PubMed/NCBI
31	Sossin WS and Barker PA: Something old, something new: BDNF-induced neuron survival requires TRPC channel function. Nat Neurosci. 10:537–538. 2007. View Article : Google Scholar : PubMed/NCBI
32	Walton MR and Dragunow I: Is CREB a key to neuronal survival? Trends Neurosci. 23:48–53. 2000. View Article : Google Scholar : PubMed/NCBI
33	Finkbeiner S: CREB couples neurotrophin signals to survival messages. Neuron. 25:11–14. 2000. View Article : Google Scholar : PubMed/NCBI
34	Chen J, Li Y and Chopp M: Intracerebral transplantation of bone marrow with BDNF after MCAo in rat. Neuropharmacology. 39:711–716. 2000. View Article : Google Scholar : PubMed/NCBI
35	Modo M, Stroemer RP, Tang E, Patel S and Hodges H: Effects of implantation site of dead stem cells in rats with stroke damage. Neuroreport. 14:39–42. 2003. View Article : Google Scholar : PubMed/NCBI