title: Melatonin reduces excitotoxic blood-brain barrier breakdown in neonatal rats.
abstract: The blood-brain barrier (BBB) is a complex structure that protects the central nervous system from peripheral insults. Understanding the molecular basis of BBB function and dysfunction holds significant potential for future strategies to prevent and treat neurological damage. The aim of our study was (1) to investigate BBB alterations following excitotoxicity and (2) to test the protective properties of melatonin. Ibotenate, a glutamate analog, was injected intracerebrally in postnatal day 5 (P5) rat pups to mimic excitotoxic injury. Animals were than randomly divided into two groups, one receiving intraperitoneal (i.p.) melatonin injections (5mg/kg), and the other phosphate buffer saline (PBS) injections. Pups were sacrificed 2, 4 and 18 h after ibotenate injection. We determined lesion size at 5 days by histology, the location and organization of tight junction (TJ) proteins by immunohistochemical studies, and BBB leakage by dextran extravasation. Expression levels of BBB genes (TJs, efflux transporters and detoxification enzymes) were determined in the cortex and choroid plexus by quantitative PCR. Dextran extravasation was seen 2h after the insult, suggesting a rapid BBB breakdown that was resolved by 4h. Extravasation was significantly reduced in melatonin-treated pups. Gene expression and immunohistochemical assays showed dynamic BBB modifications during the first 4h, partially prevented by melatonin. Lesion-size measurements confirmed white matter neuroprotection by melatonin. Our study is the first to evaluate BBB structure and function at a very early time point following excitotoxicity in neonates. Melatonin neuroprotects by preventing TJ modifications and BBB disruption at this early phase, before its previously demonstrated anti-inflammatory, antioxidant and axonal regrowth-promoting effects.
authors.affiliation: Pediatric Emergency Department, APHP, Robert Debré Hospital, Paris, France; Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France; Università degli studi di Udine, 33100 Udine, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Moretti
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Zanin
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Pansiot
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Spiri
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Manganozzi
authors.affiliation: Lyon Neurosciences Research Center, Inserm U1028, CNRS UMR5292 - Lyon University, Lyon, France.
authors.forename: I
authors.initials: I
authors.lastname: Kratzer
authors.affiliation: Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Favero
authors.affiliation: Lyon Neurosciences Research Center, Inserm U1028, CNRS UMR5292 - Lyon University, Lyon, France.
authors.forename: A
authors.initials: A
authors.lastname: Vasiljevic
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: V E
authors.initials: VE
authors.lastname: Rinaldi
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Pic
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Massano
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: D'Agostino
authors.affiliation: Perinatal Center, Dept Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Baburamani
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France.
authors.forename: M A
authors.initials: MA
authors.lastname: La Rocca
authors.affiliation: Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors.forename: L F
authors.initials: LF
authors.lastname: Rodella
authors.affiliation: Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rezzani
authors.affiliation: Perinatal Center, Dept Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Ek
authors.affiliation: Lyon Neurosciences Research Center, Inserm U1028, CNRS UMR5292 - Lyon University, Lyon, France; Brain-i, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Strazielle
authors.affiliation: Lyon Neurosciences Research Center, Inserm U1028, CNRS UMR5292 - Lyon University, Lyon, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Ghersi-Egea
authors.affiliation: Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France; Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, St. Thomas' Hospital, London, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Pediatric Emergency Department, APHP, Robert Debré Hospital, Paris, France; Inserm, U1141, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris, France; PremUP, Paris, France. Electronic address: luigi.titomanlio@rdb.aphp.fr.
authors.forename: L
authors.initials: L
authors.lastname: Titomanlio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018683:Excitatory Amino Acid Agents / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D007150:Immunohistochemistry; D008550:Melatonin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley
chemical_list: D018683:Excitatory Amino Acid Agents; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D008550:Melatonin
keywords: blood–brain barrier; brain development; ibotenate; melatonin; periventricular white matter damage