PMID- 26019015 OWN - NLM STAT- MEDLINE DCOM- 20161226 LR - 20181113 IS - 1559-1182 (Electronic) IS - 0893-7648 (Print) IS - 0893-7648 (Linking) VI - 53 IP - 4 DP - 2016 May TI - Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder. PG - 2451-2467 LID - 10.1007/s12035-015-9212-4 [doi] AB - Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced cerebrovascular pathology through the NMDA receptor. Our present study clearly signifies the therapeutic ramifications of H2S for cerebrovascular diseases such as Alzheimer's disease. Graphical Abstract ᅟ. FAU - Kamat, Pradip K AU - Kamat PK AD - Department of Physiology and Biophysics, School of Medicine, University of Louisville, and Louisville, KY 40202, USA. FAU - Kyles, Philip AU - Kyles P AD - Department of Physiology and Biophysics, School of Medicine, University of Louisville, and Louisville, KY 40202, USA. FAU - Kalani, Anuradha AU - Kalani A AD - Department of Physiology and Biophysics, School of Medicine, University of Louisville, and Louisville, KY 40202, USA. FAU - Tyagi, Neetu AU - Tyagi N AD - Department of Physiology and Biophysics, School of Medicine, University of Louisville, and Louisville, KY 40202, USA. LA - eng GR - R01 HL107640/HL/NHLBI NIH HHS/United States GR - HL107640/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150528 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Antigens, CD) RN - 0 (Cadherins) RN - 0 (Claudin-5) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (RNA, Messenger) RN - 0 (cadherin 5) RN - 0LVT1QZ0BA (Homocysteine) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) RN - YY9FVM7NSN (Hydrogen Sulfide) SB - IM MH - Alzheimer Disease/*drug therapy/genetics/*pathology/physiopathology MH - Animals MH - Antigens, CD/genetics/metabolism MH - Avoidance Learning/drug effects MH - Blood-Brain Barrier/drug effects/metabolism/*pathology/physiopathology MH - Cadherins/genetics/metabolism MH - Cerebrovascular Circulation/drug effects MH - Claudin-5/genetics/metabolism MH - Cystathionine beta-Synthase/metabolism MH - Dizocilpine Maleate/pharmacology MH - Gene Expression Regulation/drug effects MH - Glial Fibrillary Acidic Protein/genetics/metabolism MH - Homocysteine MH - Hydrogen Sulfide/pharmacology/*therapeutic use MH - Intercellular Adhesion Molecule-1/genetics/metabolism MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Memory/drug effects MH - Mice, Inbred C57BL MH - Microtubule-Associated Proteins/genetics/metabolism MH - Microvessels/drug effects/pathology MH - Nerve Tissue Proteins/genetics/metabolism MH - Permeability MH - RNA, Messenger/genetics/metabolism MH - Synapses/drug effects/*pathology PMC - PMC4662933 MID - NIHMS695099 OTO - NOTNLM OT - Alzheimer's disease OT - Blood-brain barrier dysfunction OT - Cerebrovascular pathology OT - Dementia OT - Homocysteine EDAT- 2015/05/29 06:00 MHDA- 2016/12/27 06:00 PMCR- 2017/05/01 CRDT- 2015/05/29 06:00 PHST- 2014/12/12 00:00 [received] PHST- 2015/05/05 00:00 [accepted] PHST- 2015/05/29 06:00 [entrez] PHST- 2015/05/29 06:00 [pubmed] PHST- 2016/12/27 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - 10.1007/s12035-015-9212-4 [doi] PST - ppublish SO - Mol Neurobiol. 2016 May;53(4):2451-2467. doi: 10.1007/s12035-015-9212-4. Epub 2015 May 28.