PMID- 35084654 OWN - NLM STAT- MEDLINE DCOM- 20220420 LR - 20230402 IS - 1559-1182 (Electronic) IS - 0893-7648 (Print) IS - 0893-7648 (Linking) VI - 59 IP - 4 DP - 2022 Apr TI - Cortical Dysplasia in Rats Provokes Neurovascular Alterations, GLUT1 Dysfunction, and Metabolic Disturbances That Are Sustained Post-Seizure Induction. PG - 2389-2406 LID - 10.1007/s12035-021-02624-2 [doi] AB - Focal cortical dysplasia (FCD) is associated with blood-brain barrier (BBB) dysfunction in patients with difficult-to-treat epilepsy. However, the underlying cellular and molecular factors in cortical dysplasia (CD) associated with progressive neurovascular challenges during the pro-epileptic phase, post-seizure, and during epileptogenesis remain unclear. We studied the BBB function in a rat model of congenital (in utero radiation-induced, first hit) CD and longitudinally examined the cortical brain tissues at baseline and the progressive neurovascular alterations, glucose transporter-1 (GLUT1) expression, and glucose metabolic activity at 2, 15, and 30 days following a second hit using pentylenetetrazole-induced seizure. Our study revealed through immunoblotting, immunohistochemistry, and biochemical analysis that (1) altered vascular density and prolongation of BBB albumin leakages in CD rats continued through 30 days post-seizure; (2) CD brain tissues showed elevated matrix metalloproteinase-9 levels at 2 days post-seizure and microglial overactivation through 30 days post-seizure; (3) BBB tight junction protein and GLUT1 levels were decreased and neuronal monocarboxylate transporter-2 (MCT2) and mammalian target of rapamycin (mTOR) levels were increased in the CD rat brain: (4) ATPase activity is elevated and a low glucose/high lactate imbalance exists in CD rats; and (5) the mTOR pathway is activated and MCT2 levels are elevated in the presence of high lactate during glucose starvation in vitro. Together, this study suggests that BBB dysfunction, including decreased GLUT1 expression and metabolic disturbance, may contribute to epileptogenesis in this CD rat model through multiple mechanisms that could be translated to FCD therapy in medically refractory epilepsy. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Ghosh, Chaitali AU - Ghosh C AUID- ORCID: 0000-0003-4078-0278 AD - Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. GHOSHC@ccf.org. AD - Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA. GHOSHC@ccf.org. FAU - Myers, Rosemary AU - Myers R AD - Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. FAU - O'Connor, Christina AU - O'Connor C AD - Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. FAU - Williams, Sherice AU - Williams S AD - Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. FAU - Liu, Xuefeng AU - Liu X AD - Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. FAU - Hossain, Mohammed AU - Hossain M AD - Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. FAU - Nemeth, Michael AU - Nemeth M AD - Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. FAU - Najm, Imad M AU - Najm IM AD - Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. LA - eng GR - R01 NS095825/NS/NINDS NIH HHS/United States GR - R01NS095825/NS/NINDS NIH HHS/United States GR - R01NS095825/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20220127 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Glucose Transporter Type 1) RN - 0 (Slc2a1 protein, rat) RN - 33X04XA5AT (Lactic Acid) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Blood-Brain Barrier/metabolism MH - *Epilepsy MH - Glucose/metabolism MH - Glucose Transporter Type 1/metabolism MH - Lactic Acid MH - *Malformations of Cortical Development MH - Mammals/metabolism MH - Rats MH - Seizures MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC9018620 MID - NIHMS1788173 OTO - NOTNLM OT - Blood-brain barrier OT - Epilepsy OT - Glucose transporter-1 OT - Monocarboxylate transporter-2 OT - Tight junction proteins OT - mTOR COIS- Conflict of Interest: I.N. serves on the Speaker' bureau for Eisai, Inc, and as a member of ad hoc advisory board for Eisai, Inc and Liva Nova. None of the other authors has any potential conflict of interest to disclose. EDAT- 2022/01/28 06:00 MHDA- 2022/04/21 06:00 PMCR- 2023/04/01 CRDT- 2022/01/27 12:17 PHST- 2021/07/22 00:00 [received] PHST- 2021/10/26 00:00 [accepted] PHST- 2022/01/28 06:00 [pubmed] PHST- 2022/04/21 06:00 [medline] PHST- 2022/01/27 12:17 [entrez] PHST- 2023/04/01 00:00 [pmc-release] AID - 10.1007/s12035-021-02624-2 [pii] AID - 10.1007/s12035-021-02624-2 [doi] PST - ppublish SO - Mol Neurobiol. 2022 Apr;59(4):2389-2406. doi: 10.1007/s12035-021-02624-2. Epub 2022 Jan 27.