title: Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice.
abstract: High levels of homocysteine (Hcy), known as hyperhomocysteinemia are associated with neurovascular diseases. H2S, a metabolite of Hcy, has potent anti-oxidant and anti-inflammatory activities; however, the effect of H2S has not been explored in Hcy (IC)-induced neurodegeneration and neurovascular dysfunction in mice. Therefore, the present study was designed to explore the neuroprotective role of H2S on Hcy-induced neurodegeneration and neurovascular dysfunction. To test this hypothesis we employed wild-type (WT) males ages 8-10 weeks, WT+artificial cerebrospinal fluid (aCSF), WT+Hcy (0.5 μmol/μl) intracerebral injection (IC, one time only prior to NaHS treatment), WT+Hcy+NaHS (sodium hydrogen sulfide, precursor of H2S, 30 μmol/kg, body weight). NaHS was injected i.p. once daily for the period of 7 days after the Hcy (IC) injection. Hcy treatment significantly increased malondialdehyde, nitrite level, acetylcholinestrase activity, tumor necrosis factor-alpha, interleukin-1 beta, glial fibrillary acidic protein, inducible nitric oxide synthase, endothelial nitric oxide synthase and decreased glutathione level indicating oxidative-nitrosative stress and neuroinflammation as compared to control and aCSF-treated groups. Further, increased expression of neuron-specific enolase, S100B and decreased expression of (post-synaptic density-95, synaptosome-associated protein-97) synaptic protein indicated neurodegeneration. Brain sections of Hcy-treated mice showed damage in the cortical area and periventricular cells. Terminal deoxynucleotidyl transferase-mediated, dUTP nick-end labeling-positive cells and Fluro Jade-C staining indicated apoptosis and neurodegeneration. The increased expression of matrix metalloproteinase (MMP) MMP9, MMP2 and decreased expression of tissue inhibitor of metalloproteinase (TIMP) TIMP-1, TIMP-2, tight junction proteins (zonula occulden 1) in Hcy-treated group indicate neurovascular remodeling. Interestingly, NaHS treatment significantly attenuated Hcy-induced oxidative stress, memory deficit, neurodegeneration, neuroinflammation and cerebrovascular remodeling. The results indicate that H2S is effective in providing protection against neurodegeneration and neurovascular dysfunction.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Kamat
authors.forename: A
authors.initials: A
authors.lastname: Kalani
authors.forename: S
authors.initials: S
authors.lastname: Givvimani
authors.forename: P B
authors.initials: PB
authors.lastname: Sathnur
authors.forename: S C
authors.initials: SC
authors.lastname: Tyagi
authors.forename: N
authors.initials: N
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D064426:Gasotransmitters / Q000008:administration & dosage / Q000378:metabolism*; D006710:Homocysteine / Q000008:administration & dosage / Q000633:toxicity; D006862:Hydrogen Sulfide / Q000008:administration & dosage / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064426:Gasotransmitters; D006710:Homocysteine; D006862:Hydrogen Sulfide
keywords: 5,5′-dithiobis-(2-nitrobenzoic acid); AChE; AD; Alzheimer’s diseases; BBB; DI; DTNB; ECM; EDTA; FJC; Fluro Jade-C; GFAP; GSH; H(2)S; HE; HRP; Hcy; Hematoxylin and Eosin; IC; IL; MDA; MMP; NSE; PBS; PD; PMSF; PSD95; PVDF; Parkinson’s disease; RI; RIPA; RT-PCR; SAP97; TBS-T; TCA; TIMP; TJPs; TNF; TUNEL; Tris-buffered saline with Tween 20; WT; ZO; aCSF; acetylcholinesterase; artificial cerebrospinal fluid; blood–brain barrier; cerebrovascular dysfunction; discrimination index; eNOS; endothelial nitric oxide synthase; ethylenediaminetetraacetic acid; extracellular matrix; glial fibrillary acidic protein; glutathione; homocysteine; horseradish peroxidase; iNOS; inducible nitric oxide synthase; interleukin; intracerebral; malondialdehyde; matrix metalloproteinases; neurodegeneration; neuroinflammation; neuron-specific enolase; phenylmethylsulfonyl fluoride; phosphate-buffered saline; polyvinylidene difluoride; post-synaptic density-95; radio immunoprecipitation assay; recognition index; reverse transcription polymerase chain reaction; synaptosome associated protein-97; terminal deoxynucleotidyl transferase-mediated, dUTP nick-end labeling; tight junction proteins; tissue inhibitor of metalloproteinases; trichloroacetic acid; tumor necrosis factor; wild type; zonula occuldens
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