Cocaine‑ and amphetamine‑regulated transcript (CART) is associated with dopamine and is protective against ischemic stroke

Lin,Lili; Sun,Da; Chang,Jing; Ma,Ming; Zhou,Xiaoying; Zhao,Min; Li,Jian

doi:10.3892/mmr.2018.9296

Cocaine‑ and amphetamine‑regulated transcript (CART) is associated with dopamine and is protective against ischemic stroke

Authors:
- Lili Lin
- Da Sun
- Jing Chang
- Ming Ma
- Xiaoying Zhou
- Min Zhao
- Jian Li
View Affiliations

Affiliations: Department of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi, Jiangsu 214028, P.R. China, Department of Nursing, Wuxi Higher Health Vocational Technology School, Wuxi, Jiangsu 214028, P.R. China, Department of Cardiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, P.R. China
Published online on: July 19, 2018 https://doi.org/10.3892/mmr.2018.9296
Pages: 3298-3304
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cocaine and amphetamine‑regulated transcript (CART) is a neuropeptide that can protect brains against ischemic injury. The aim of the present study was to investigate the effects of the CART within ischemic stroke and it possible mechanism. The expression levels of dopamine (DA) and CART in ischemic brain tissues of mice were measured following middle cerebral artery occlusion (MCAO). After receiving the treatment of DA and CART, the infarct volume of brain was measured in mice with MCAO. In addition, the function and potential mechanism of CART in ischemic stroke were further investigated. DA and CART expression was significantly decreased in mice with MCAO compared with normal control mice. Treatment of mice with MCAO with exogenous CART significantly decreased the extent of brain injury compared with untreated mice with MCAO. Treatment with exogenous CART promoted the survival of ex vivo neurons following oxygen‑glucose deprivation (OGD), while exogenous DA induced CART mRNA expression in a dose‑dependent manner, which suggested an association between CART and DA. Apoptosis of ex vivo neurons was significantly increased following OGD, however treatment with exogenous CART significantly inhibited this effect. The potential mechanism of CART was determined to be associated with inflammatory cytokines and related apoptotic genes. CART therefore appears to be associated with DA in its effect on ischemic stroke and is protective against brain injury following ischemic stroke by reducing inflammation activation; it may provide a promising means to treat ischemic stroke patients.

View Figures

View References

1	Douglass J, McKinzie AA and Couceyro P: PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci. 15:2471–2481. 1995. View Article : Google Scholar : PubMed/NCBI
2	Wierup N, Kuhar M, Nilsson BO, Mulder H, Ekblad E and Sundler F: Cocaine- and amphetamine-regulated transcript (CART) is expressed in several islet cell types during rat development. J Histochem Cytochem. 52:169–177. 2004. View Article : Google Scholar : PubMed/NCBI
3	Rogge G, Jones D, Hubert GW, Lin Y and Kuhar MJ: CART peptides: Regulators of body weight, reward and other functions. Nat Rev Neurosci. 9:747–758. 2008. View Article : Google Scholar : PubMed/NCBI
4	Wu B, Hu S, Yang M, Pan H and Zhu S: CART peptide promotes the survival of hippocampal neurons by upregulating brain-derived neurotrophic factor. Biochem Biophys Res Commun. 347:656–661. 2006. View Article : Google Scholar : PubMed/NCBI
5	Mao P, Ardeshiri A, Jacks R, Yang S, Hurn PD and Alkayed NJ: Mitochondrial mechanism of neuroprotection by CART. Eur J Neurosci. 26:624–632. 2007. View Article : Google Scholar : PubMed/NCBI
6	Jia J, Chen X, Zhu W, Luo Y, Hua Z and Xu Y: CART protects brain from damage through ERK activation in ischemic stroke. Neuropeptides. 42:653–661. 2008. View Article : Google Scholar : PubMed/NCBI
7	Luo Y, Shen H, Liu HS, Yu SJ, Reiner DJ, Harvey BK, Hoffer BJ, Yang Y and Wang Y: CART peptide induces neuroregeneration in stroke rats. J Cereb Blood Flow Metab. 33:300–310. 2013. View Article : Google Scholar : PubMed/NCBI
8	Hosp JA, Pekanovic A, Rioult-Pedotti MS and Luft A: Dopaminergic projections from midbrain to primary motor cortex mediate motor skill learning. J Neurosci. 31:2481–2487. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kawashima S, Ueki Y, Kato T, Matsukawa N, Mima T, Hallett M, Ito K and Ojika K: Changes in striatal dopamine release associated with human motor-skill acquisition. PLoS One. 7:e317282012. View Article : Google Scholar : PubMed/NCBI
10	Calne DB and Sandler M: L-Dopa and parkinsonism. Nature. 226:21–24. 1970. View Article : Google Scholar : PubMed/NCBI
11	Bhakta BB, Hartley S, Holloway I, Couzens JA, Ford GA, Meads D, Sackley CM, Walker MF, Ruddock SP and Farrin AJ: The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke. Trials. 15:3162014. View Article : Google Scholar : PubMed/NCBI
12	Brannan T, Weinberger J, Knott P, Taff I, Kaufmann H, Togasaki D, Nieves-Rosa J and Maker H: Direct evidence of acute, massive striatal dopamine release in gerbils with unilateral strokes. Stroke. 18:108–110. 1987. View Article : Google Scholar : PubMed/NCBI
13	Shin SS, Bray ER, Zhang CQ and Dixon CE: Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats. Brain Res. 1369:208–215. 2011. View Article : Google Scholar : PubMed/NCBI
14	Krysiak R, Kedzia A and Okopień B: The effect of oxcarbamazepine on the clinical effectiveness of dopamine agonists in the treatment of prolactinoma. Wiad Lek. 64:279–282. 2011.PubMed/NCBI
15	Ruscher K, Kuric E and Wieloch T: Levodopa treatment improves functional recovery after experimental stroke. Stroke. 43:507–513. 2012. View Article : Google Scholar : PubMed/NCBI
16	PD Med Collaborative Group, . Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, McIntosh E, Wheatley K, Williams A and Clarke CE: Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): A large, open-label, pragmatic randomised trial. Lancet. 384:1196–1205. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sami MB and Faruqui R: The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke. Acta Neuropsychiatr. 27:317–326. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zhao H, Cheng L, Liu Y, Zhang W, Maharjan S, Cui Z, Wang X, Tang D and Nie L: Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: Inhibition of JNK signaling in lipopolysaccharide-induced microglia. J Mol Neurosci. 52:186–192. 2014. View Article : Google Scholar : PubMed/NCBI
19	Xu Y, Zhang W, Klaus J, Young J, Koerner I, Sheldahl LC, Hurn PD, Martínez-Murillo F and Alkayed NJ: Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection. Proc Natl Acad Sci USA. 103:14489–14494. 2006. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Qing K and Chen Y: Central CART gene delivery by recombinant AAV vector attenuates body weight gain in diet-induced-obese rats. Regul Pept. 140:21–26. 2007. View Article : Google Scholar : PubMed/NCBI
22	Zhang M, Han L and Xu Y: Roles of cocaine- and amphetamine-regulated transcript in the central nervous system. Clin Exp Pharmacol Physiol. 39:586–592. 2012. View Article : Google Scholar : PubMed/NCBI
23	Chang L, Chen Y, Li J, Liu Z, Wang Z, Chen J, Cao W and Xu Y: Cocaine- and amphetamine-regulated transcript modulates peripheral immunity and protects against brain injury in experimental stroke. Brain Behav Immun. 25:260–269. 2011. View Article : Google Scholar : PubMed/NCBI
24	Szeto HH: Mitochondria-targeted peptide antioxidants: Novel neuroprotective agents. AAPS J. 8:E521–E531. 2006. View Article : Google Scholar : PubMed/NCBI
25	Turrens JF: Mitochondrial formation of reactive oxygen species. J Physiol. 552:335–344. 2003. View Article : Google Scholar : PubMed/NCBI