{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:33:25Z","timestamp":1789439605397,"version":"build-2803163510"},"reference-count":61,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T00:00:00Z","timestamp":1385510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The endocannabinoid system is a component of the neuroprotective mechanisms that an organism displays after traumatic brain injury (TBI). A diurnal variation in several components of this system has been reported. This variation may influence the recovery and survival rate after TBI. We have previously reported that the recovery and survival rate of rats is higher if TBI occurs at 1:00 than at 13:00. This could be explained by a diurnal variation of the endocannabinoid system. Here, we describe the effects of anandamide administration in rats prior to the induction of TBI at two different times of the day: 1:00 and 13:00. We found that anandamide reduced the neurological damage at both times. Nevertheless, its effects on bleeding, survival, food intake, and body weight were dependent on the time of TBI. In addition, we analyzed the diurnal variation of the expression of the cannabinoid receptors CB1R and CB2R in the cerebral cortex of both control rats and rats subjected to TBI. We found that CB1R protein was expressed more during the day, whereas its mRNA level was higher during the night. We did not find a diurnal variation for the CB2R. In addition, we also found that TBI increased CB1R and CB2R in the contralateral hemisphere and disrupted the CB1R diurnal cycle.<\/jats:p>","DOI":"10.3390\/ijms141223341","type":"journal-article","created":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T14:43:20Z","timestamp":1385563400000},"page":"23341-23355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Does the Neuroprotective Role of Anandamide Display  Diurnal Variations?"],"prefix":"10.3390","volume":"14","author":[{"given":"Marina","family":"Martinez-Vargas","sequence":"first","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Morales-Gomez","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Gonzalez-Rivera","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Hernandez-Enriquez","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adan","family":"Perez-Arredondo","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Estrada-Rojo","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz","family":"Navarro","sequence":"additional","affiliation":[{"name":"Physiology Department, School of Medicine, Universidad Nacional Autonoma de Mexico, AP 70-250, Mexico D.F. 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S1471-4914(02)02276-1","article-title":"Cannabinoids and brain injury: Therapeutic implications","volume":"8","author":"Mechoulam","year":"2002","journal-title":"Trends Mol. Med"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/sj.jcbfm.9600047","article-title":"CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition","volume":"25","author":"Panikashvili","year":"2005","journal-title":"J. Cereb. Blood Flow Metab"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.nbd.2005.11.004","article-title":"The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines","volume":"22","author":"Panikashvili","year":"2006","journal-title":"Neurobiol. Dis"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12035-007-8008-6","article-title":"Endocannabinoids and traumatic brain injury","volume":"36","author":"Mechoulam","year":"2007","journal-title":"Mol. Neurobiol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0165-0173(02)00157-1","article-title":"Cerebral ischemia and trauma different etiologies yet similar mechanisms: Neuroprotective opportunities","volume":"39","author":"Leker","year":"2002","journal-title":"Brain Res. Rev"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/0002-9343(88)90231-8","article-title":"Epidemiology of nocturnal asthma","volume":"85","author":"Turner","year":"1988","journal-title":"Am. J. Med"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"326","DOI":"10.3949\/ccjm.59.3.326","article-title":"Circadian rhythms and migraine","volume":"59","author":"Solomon","year":"1992","journal-title":"Cleve Clin. J. Med"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1056\/NEJM198511213132103","article-title":"Circadian variation in the frequency of onset of acute myocardial infarction","volume":"313","author":"Muller","year":"1985","journal-title":"N. Engl. J. Med"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1161\/01.STR.8.2.230","article-title":"Diurnal variation in occurrence of strokes","volume":"8","author":"Marshall","year":"1977","journal-title":"Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3109\/07420529109059168","article-title":"Circadian variation in the onset of acute cerebral ischemia: Ethiopathogenetic correlates in 80 patients given angiography","volume":"8","author":"Toni","year":"1991","journal-title":"Chronobiol. Int"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3171\/jns.2000.93.1.0082","article-title":"Temporal changes in sensitivity of rats to cerebral ischemic insult","volume":"93","author":"Vinall","year":"2000","journal-title":"J. Neurosurg"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neulet.2006.02.010","article-title":"Recovery after a traumatic brain injury depends on diurnal variations. Effect of cystatin C","volume":"400","author":"Navarro","year":"2006","journal-title":"Neurosci. Lett"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0306-4522(02)00820-5","article-title":"Sleep modulates cannabinoid receptor 1 expression in the pons of rats","volume":"117","author":"Landa","year":"2003","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00213-007-0911-z","article-title":"A potential function of endocannabinoids in the selection of a navigation strategy by rats","volume":"198","author":"Galicia","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s00018-003-3453-5","article-title":"Differential diurnal variations of anandamide and 2-arachidonoyl-glycerol levels in rat brain","volume":"61","author":"Valenti","year":"2004","journal-title":"Cell Mol. Life Sci"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.lfs.2005.12.028","article-title":"Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat","volume":"79","year":"2006","journal-title":"Life Sci"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.neuroscience.2009.06.043","article-title":"Temporal changes in mouse brain fatty acid amide hydrolase activity","volume":"163","author":"Glaser","year":"2009","journal-title":"Neuroscience"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/cne.21383","article-title":"Distribution of type I cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamous","volume":"503","author":"Wittmann","year":"2007","journal-title":"J. Comp. Neurol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10061","DOI":"10.1523\/JNEUROSCI.5838-09.2010","article-title":"Cannabinoids excite circadian clock neurons","volume":"30","author":"Acuna","year":"2010","journal-title":"J. Neurosci"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.brainres.2008.05.048","article-title":"Cannabinoids and hamster circadian activity rhythms","volume":"1222","author":"Sanford","year":"2008","journal-title":"Brain Res"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1055\/s-0029-1214145","article-title":"Circadian variation within hemostasis: An underrecognized link between biology and disease?","volume":"35","author":"Montagnana","year":"2009","journal-title":"Semin. Thromb. Hemost"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1016\/0024-3205(89)90015-5","article-title":"Circadian rhythms of blood clotting time and coagulation factors II, VII, IX and X in rats","volume":"45","author":"Soulban","year":"1989","journal-title":"Life Sci"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0014-5793(99)00308-7","article-title":"Anandamide activates human platelets through a pathway independent of the arachidonate cascade","volume":"447","author":"Maccarrone","year":"1999","journal-title":"FEBS Lett"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S0014-5793(00)01359-4","article-title":"Activation of rabbit blood platelets by anandamide through its cleavage into arachidonic acid","volume":"471","author":"Braud","year":"2000","journal-title":"FEBS Lett"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"M156","DOI":"10.12968\/hmed.2009.70.Sup10.44641","article-title":"Understanding the metabolic response to trauma","volume":"70","author":"Sritharan","year":"2009","journal-title":"Br. J. Hosp. Med"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0006-8993(03)03525-X","article-title":"Neuroprotective effects of insulin-like growth factor-I (IGF-I) following a penetrating brain injury in rats","volume":"991","author":"Kazanis","year":"2003","journal-title":"Brain Res"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2174\/1389450053174514","article-title":"Cannabinoids and the regulation of ingestive behavior","volume":"6","author":"Vickers","year":"2005","journal-title":"Curr. Drug Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0014-5793(95)01194-J","article-title":"Occurrence and postmortem generation of anandamide and other long-chain N-acylethanolamines in mammalian brain","volume":"375","author":"Schmid","year":"1995","journal-title":"FEBS Lett"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1124\/mol.54.3.459","article-title":"Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity","volume":"54","author":"Shen","year":"1998","journal-title":"Mol. Pharmacol"},{"key":"ref_30","first-page":"2987","article-title":"Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures","volume":"19","author":"Nagayama","year":"1999","journal-title":"J. Neuroci"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.brainres.2008.09.019","article-title":"Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia","volume":"1240","author":"Schomacher","year":"2008","journal-title":"Brain Res"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1097\/00001756-199209000-00022","article-title":"Circadian rhythms of vasopressin content in the suprachiasmatic nucleus of the rat","volume":"3","author":"Tominaga","year":"1992","journal-title":"Neuroreport"},{"key":"ref_33","first-page":"157","article-title":"Diurnal variation in vasopressin and oxytocin messenger RNAs in hypothalamic nuclei of the rat","volume":"464","author":"Burbach","year":"1988","journal-title":"Brain Res"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0024-3205(83)90708-7","article-title":"Ontogeny of diurnal rhythms of central dopamine, serotonin and spirodecanone bindings sites and of motor activity in the rat","volume":"33","author":"Bruinink","year":"1983","journal-title":"Life Sci"},{"key":"ref_35","first-page":"831","article-title":"Seasonal variations in the endogenous rhythm of dopamine receptor binding in rat striatum","volume":"16","author":"Naber","year":"1981","journal-title":"Biol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1076\/brhm.29.5.538.4817","article-title":"Diurnal variations of striatal D2 dopaminergic receptors and its relation with haloperidol-induced catalepsy","volume":"29","author":"Torner","year":"1998","journal-title":"Biol. Rhythm Res"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/42015","article-title":"A second endogenous cannabinoid that modulates long-term potentiation","volume":"388","author":"Stella","year":"1997","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/(SICI)1098-2396(199811)30:3<298::AID-SYN7>3.0.CO;2-6","article-title":"Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to delta-9-tethahydrocannabinol","volume":"30","author":"Romero","year":"1998","journal-title":"Synapse"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0169-328X(98)00232-0","article-title":"Effects of long-term exposure to delta-9-THC on expression of cannabinoid receptor (CB1) mRNA in different brain regions","volume":"62","author":"Zhuang","year":"1998","journal-title":"Mol. Brain Res"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1189\/jlb.0306224","article-title":"Transcriptional regulation of the cannabinoid receptor type 1 gene in T cells by cannabinoids","volume":"81","author":"Borner","year":"2007","journal-title":"J. Leukoc. Biol"},{"key":"ref_41","first-page":"282","article-title":"Gene expression patterns following unilateral traumatic brain injury reveals a local proinflammatory and remote anti-inflammatory response","volume":"14","author":"White","year":"2013","journal-title":"Genomics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.nbd.2008.09.015","article-title":"The endocannabinoid system is modulated in response to spinal cord injury in rats","volume":"33","author":"Petrosino","year":"2009","journal-title":"Neurobiol. Dis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/1531-8249(200008)48:2<257::AID-ANA18>3.0.CO;2-P","article-title":"CB1 cannabinoid receptor induction in experimental stroke","volume":"48","author":"Jin","year":"2000","journal-title":"Ann. Neurol"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00401-005-1109-2","article-title":"Short-term ischemia usually used for ischemic preconditioning down-regulates central cannabinoid receptors in the gerbil hippocampus","volume":"111","author":"Schomacher","year":"2006","journal-title":"Acta Neuropathol"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.neuroscience.2008.01.022","article-title":"Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic\/reperfusion injury","volume":"152","author":"Zhang","year":"2008","journal-title":"Neuroscience"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1080\/07420520601142569","article-title":"Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury","volume":"24","author":"Paul","year":"2007","journal-title":"Chronobiol. Int"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s12028-010-9399-1","article-title":"Loss of cortisol circadian rhythm in patients with traumatic brain injury: A microdialysis evaluation","volume":"13","author":"Perez","year":"2010","journal-title":"Neurocrit. Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1212\/01.wnl.0000258672.52836.30","article-title":"Circadian rhythm sleep disorders following mild traumatic brain injury","volume":"68","author":"Ayalon","year":"2007","journal-title":"Neurology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2165\/11584870-000000000-00000","article-title":"Sleep disorders in patients with traumatic brain injury: A review","volume":"25","author":"Castriotta","year":"2010","journal-title":"CNS Drugs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e46204","DOI":"10.1371\/journal.pone.0046204","article-title":"Traumatic brain injury-induced dysregulation of the circadian clock","volume":"7","author":"Boone","year":"2012","journal-title":"PLoS One"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3791","DOI":"10.1097\/00001756-200112040-00038","article-title":"Delta-9-tetrahydrocannabinol increases brain temperature and inverts circadian","volume":"12","author":"Perron","year":"2001","journal-title":"Neuroreport"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0006-8993(93)90220-H","article-title":"Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: A quantitative autoradiographic study","volume":"616","author":"Oviedo","year":"1993","journal-title":"Brain Res"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0091-3057(94)90108-2","article-title":"Down-regulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol","volume":"47","author":"Gorriti","year":"1994","journal-title":"Pharmacol. Biochem. Behav"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.brainres.2008.12.037","article-title":"Long-term consequences of URB597 administration during adolescence on cannabinoid CB1 receptor binding in brain areas","volume":"1257","author":"Marco","year":"2009","journal-title":"Brain Res"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1523\/JNEUROSCI.21-07-02425.2001","article-title":"Agonist-induced internalization and trafficking of cannabinoid CB1 receptors in hippocampal neurons","volume":"21","author":"Coutts","year":"2001","journal-title":"J. Neurosci"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/0091-3057(95)00023-P","article-title":"Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to delta 9-tetrahydrocannabinol","volume":"51","author":"Romero","year":"1995","journal-title":"Pharmacol. Biochem. Behav"},{"key":"ref_57","first-page":"84","article-title":"The combination of selective inhibition of the cannabinoid CB1 receptor and activation of the cannabinoid CB2 receptor yields improved attenuation of motor and autonomic deficits in a mouse model of spinal cord injury","volume":"56","author":"Heller","year":"2009","journal-title":"Clin. Neurosurg"},{"key":"ref_58","unstructured":"Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, Academic Press. [4th ed.]."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/S0006-8993(98)00969-X","article-title":"Anandamida modulates sleep and memory in rats","volume":"812","author":"Navarro","year":"1998","journal-title":"Brain Res"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S0028-3908(99)00262-2","article-title":"Functional assessments in mice and rats after focal stroke","volume":"39","author":"Hunter","year":"2000","journal-title":"Neuropharmacology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/12\/23341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:50:56Z","timestamp":1760219456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/12\/23341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,27]]},"references-count":61,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["ijms141223341"],"URL":"https:\/\/doi.org\/10.3390\/ijms141223341","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11,27]]}}}