Ketones Prevent Oxidative Impairment of Hippocampal Synaptic Integrity through KATP Channels
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{"title"=>"Ketones prevent oxidative impairment of hippocampal synaptic integrity through K<inf>ATP</inf> channels", "type"=>"journal", "authors"=>[{"first_name"=>"Do Young", "last_name"=>"Kim", "scopus_author_id"=>"56109746400"}, {"first_name"=>"Mohammed G.", "last_name"=>"Abdelwahab", "scopus_author_id"=>"36545757700"}, {"first_name"=>"Soo Han", "last_name"=>"Lee", "scopus_author_id"=>"56329827000"}, {"first_name"=>"Derek", "last_name"=>"O'Neill", "scopus_author_id"=>"37077648300"}, {"first_name"=>"Roger J.", "last_name"=>"Thompson", "scopus_author_id"=>"7406368612"}, {"first_name"=>"Henry J.", "last_name"=>"Duff", "scopus_author_id"=>"7006330191"}, {"first_name"=>"Patrick G.", "last_name"=>"Sullivan", "scopus_author_id"=>"7402033421"}, {"first_name"=>"Jong M.", "last_name"=>"Rho", "scopus_author_id"=>"7102472905"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84929991757", "doi"=>"10.1371/journal.pone.0119316", "pui"=>"604108392", "issn"=>"19326203", "pmid"=>"25848768", "scopus"=>"2-s2.0-84929991757"}, "id"=>"2cfad438-c847-329c-a4f7-858eac721a88", "abstract"=>"Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (KATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of KATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the KATP channel activator diazoxide. Inhibition of KATP channels reversed ketone-evoked hippocampal protection, and genetic ablation of the inwardly rectifying K+ channel subunit Kir6.2, a critical component of KATP channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the KATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of KATP channels.", "link"=>"http://www.mendeley.com/research/ketones-prevent-oxidative-impairment-hippocampal-synaptic-integrity-through-kinfatpinf-channels", "reader_count"=>14, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Master"=>4, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Master"=>4, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Nursing and Health Professions"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>3, "Neuroscience"=>5}, "reader_count_by_subdiscipline"=>{"Neuroscience"=>{"Neuroscience"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Italy"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2006814"], "description"=>"<p>(A) Changes in PS amplitude (as % of baseline) during or after drug application under different experimental conditions. No changes were seen in the PS amplitude during infusion with 200 μM 5HD alone or 5HD with 300 μM DZ and H<sub>2</sub>O<sub>2</sub>. There was a reversible, dose-dependent blockade by 5HD of the PS when either ketones or 100 μM DZ were applied concurrently with H<sub>2</sub>O<sub>2</sub>. Asterisks denote significant differences between experimental groups and the control at a specific time-point (*** <i>p</i> < 0.001). The dotted line indicates the mean PS amplitude of the control group. Each horizontal bar indicates mean PS amplitude ± SEM obtained in 12 slices from 5 rats. (B) Normal TBS-induced LTP was seen with 200 μM 5HD. However, LTP was impaired when either ketones or 100 μM DZ were administered together with 5-HD; the EPSP amplitude was measured 110 ± 9% and 115 ± 11% at 50 min post-TBS, respectively. Asterisks denote significant differences between 200 μM 5-HD alone and other treatment groups (**, <i>p</i><0.01). Each LTP dataset was collected in 10 hippocampal slices. (C) Time-course of the MTT assay for cell viability in murine hippocampal HT22 cells treated with H<sub>2</sub>O<sub>2</sub>—with or without application of BHB or ACA (each 3 mM)—for 3, 6, 12, and 24 hours. Each vertical bar indicates the mean ± SEM (n = 30). (D) Representative photomicrographs of HT22 cells under control conditions, with H<sub>2</sub>O<sub>2</sub>, or when H<sub>2</sub>O<sub>2</sub> was co-treated with ACA at two time-points (0 and 24 hrs). (E) Oxidative-induced cell death in HT22 cells measured under different treatment conditions. While 20 μM and 200 μM 5HD alone had no influence on cell viability, ketone (each 1 mM)-mediated neuronal protection against oxidative injury was completely negated by 200 μM 5HD. (F) Bar graphs illustrating changes in ATP levels in hippocampal CA1 samples treated with ketones with or without 5-HD on H<sub>2</sub>O<sub>2</sub>-induced oxidative stress after 2 hrs. ATP levels represented as % of control are mean ± SEM of 12 slices analyzed after 2 hr with indicated significant decreases (**<i>p</i> < 0.01) compared with control group, which was infused with physiological saline under similar experimental conditions.</p>", "links"=>[], "tags"=>["KATP channel activation", "Hippocampal Synaptic Integrity", "KATP channel activator diazoxide", "KATP channels", "synaptic protection", "hippocampal synaptic protection", "hd", "exogenous oxidative stress", "kd", "ketone"], "article_id"=>1368886, "categories"=>["Biological Sciences"], "users"=>["Do Young Kim", "Mohammed G. Abdelwahab", "Soo Han Lee", "Derek O’Neill", "Roger J. Thompson", "Henry J. Duff", "Patrick G. Sullivan", "Jong M. Rho"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119316.g003", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pharmacological_blockade_of_K_ATP_channels_negates_the_hippocampal_synaptic_and_neuronal_protection_afforded_by_ketones_/1368886", "title"=>"Pharmacological blockade of K<sub>ATP</sub> channels negates the hippocampal synaptic and neuronal protection afforded by ketones.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-07 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/2006811"], "description"=>"<p>(A) Representative traces of DZ (100 μM or 300 μM) with 2 mM H<sub>2</sub>O<sub>2</sub> on the CA1 hippocampal PS, demonstrating the dose-dependent synaptic protective effects of DZ. Partial protection was seen with H<sub>2</sub>O<sub>2</sub> exposure following a 10 min pre-incubation with 100 μM DZ (<i>middle</i>). No significant differences were found between the two groups (co-application <i>vs</i>. pre-incubation) compared to 300 μM DZ. (B) Summary of PS amplitude changes (as % baseline) during or after drug application is shown in the bar graph. Each vertical bar indicates mean PS amplitude ± SEM, and was obtained in 12 slices from 5 rats. Asterisks denote significant differences between the 100 μM DZ plus 2 mM H<sub>2</sub>O<sub>2</sub> group and other treatment groups (**, <i>p</i> < 0.01). (C) DZ protects synaptic impairment against oxidative stress. Representative traces of EPSPs at respective time-points (a, b, c) are depicted on the right. (D) Changes in paired-pulse facilitation at CA1 in hippocampal slices after 40 min infusion of physiological saline, KBs (a cocktail of BHB and ACA; each 1 mM) and 100 μM DZ. Exposure to either KBs or DZ did not induce a significant change in presynaptic transmission following paired-pulse stimulation. The data was obtained in 7 slices from 4 mice. ISI indicated interstimulus interval.</p>", "links"=>[], "tags"=>["KATP channel activation", "Hippocampal Synaptic Integrity", "KATP channel activator diazoxide", "KATP channels", "synaptic protection", "hippocampal synaptic protection", "hd", "exogenous oxidative stress", "kd", "ketone"], "article_id"=>1368883, "categories"=>["Biological Sciences"], "users"=>["Do Young Kim", "Mohammed G. Abdelwahab", "Soo Han Lee", "Derek O’Neill", "Roger J. Thompson", "Henry J. Duff", "Patrick G. Sullivan", "Jong M. Rho"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119316.g002", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Diazoxide_mimics_the_synaptic_effect_of_ketones_/1368883", "title"=>"Diazoxide mimics the synaptic effect of ketones.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-07 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/2006817"], "description"=>"<p>(A) TBS-evoked intact LTP in wild–type slices decayed to baseline levels 60 min after H<sub>2</sub>O<sub>2</sub> application but was maintained in slices incubated with either ketones or DZ (n = 10 slices; 5 WT mice; *** <i>p</i> < 0.001). (B) Loss of functional Kir6.2 channels did not affect TBS-induced LTP. However, LTP in Kir6.2 KO slices was impaired by H<sub>2</sub>O<sub>2</sub> to a basal level indistinguishable from WT slices exposed to H<sub>2</sub>O<sub>2</sub>. (C) Partial blockade of LTP in Kir6.2 KO mice. Changes in LTP from Kir6.2 KO slices were observed in the presence of either ketones (ACA and BHB, each 1 mM) or DZ (100 μM) with H<sub>2</sub>O<sub>2</sub> (200 μM). In contrast, addition of 5-HD in this condition resulted in the complete blockade of LTP formation (n = 8 slices from 4 KO mice). (D) Pharmacological blockade of sK<sub>ATP</sub> channels with glibenclamide (Glb; 10 μM) did not significantly alter LTP formation, although it did produce a slight reduction in the EPSP amplitude post-TBS. When Glb was bath-applied, LTP impairment induced by H<sub>2</sub>O<sub>2</sub> was not fully reversed by ketone application. (E) Bar graph summarizing mean EPSP amplitudes (±SEM) at 60 min after TBS in various treatment groups involving KO mice and WT mice. ANOVA followed by Tukey test; * <i>p</i> < 0.05; ** <i>p</i> <0.01. N.S. = not significant.</p>", "links"=>[], "tags"=>["KATP channel activation", "Hippocampal Synaptic Integrity", "KATP channel activator diazoxide", "KATP channels", "synaptic protection", "hippocampal synaptic protection", "hd", "exogenous oxidative stress", "kd", "ketone"], "article_id"=>1368889, "categories"=>["Biological Sciences"], "users"=>["Do Young Kim", "Mohammed G. Abdelwahab", "Soo Han Lee", "Derek O’Neill", "Roger J. Thompson", "Henry J. Duff", "Patrick G. Sullivan", "Jong M. Rho"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119316.g004", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Both_mitochondrial_and_surface_K_ATP_channels_are_necessary_for_ketone_mediated_synaptic_protection_/1368889", "title"=>"Both mitochondrial- and surface- K<sub>ATP</sub> channels are necessary for ketone-mediated synaptic protection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-07 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/2006810"], "description"=>"<p>(A) LTP recorded in rat CA1 hippocampal slices exposed to various concentrations of H<sub>2</sub>O<sub>2</sub>. Theta-burst stimulation (TBS) of schaffer collaterals led to robust LTP changes when either ACA or BHB (3 mM each) were perfused, but not with either 200 μM or 2 mM H<sub>2</sub>O<sub>2</sub>. Representative traces of excitatory post-synaptic potentials (EPSPs) at respective time-points (a, b, c) depicted on the right of each panel. Vertical arrows in this and following figures indicate the time-point of TBS initiation. Dotted line denotes the baseline field potential amplitude which is the mean EPSP during a 10 min physiological saline infusion. (B) Only partial inhibition of LTP was observed when 200 μM H<sub>2</sub>O<sub>2</sub> was co-applied with either ACA or BHB (1 mM each). (C) Intact LTP formation was seen when a cocktail of ketones (BHB and ACA, 1mM each) was used in conjunction with 200 μM H<sub>2</sub>O<sub>2</sub>, but not with 2 mM H<sub>2</sub>O<sub>2</sub>. (D) Summary bar graph indicating changes in EPSP amplitudes at 60 min after TBS amongst various treatment groups. Dose-dependent protection by ketones against LTP impairment by H<sub>2</sub>O<sub>2</sub>-induced oxidative stress was seen in these experiments. Each vertical bar represents the EPSP amplitude ± SEM (obtained in 10 slices from 5 rats). One way ANOVA followed by Tukey <i>post-hoc</i> analysis; *, <i>p</i> <0.05; ** or <sup>##</sup>, <i>p</i> < 0.01, NS, not significant. (E) Acute application of H<sub>2</sub>O<sub>2</sub> results in depression of the population spike (PS) in stratum pyramidale of Cornu Ammonis (CA)1. Shown are changes in the mean (± SEM) PS amplitude before, during, or after H<sub>2</sub>O<sub>2</sub> infusion, but only when 2 mM H<sub>2</sub>O<sub>2</sub> was used. Representative traces of the PS alone (<i>top</i>), or co-applied with 2 mM H<sub>2</sub>O<sub>2</sub> (<i>middle</i>) or 2 mM H<sub>2</sub>O<sub>2</sub> (<i>bottom</i>) depicted on the right. Pre-incubation with ketones potentiated the restoration of PS amplitude compared to co-application of ketones with H<sub>2</sub>O<sub>2.</sub> (F) Summary of amplitude changes in the PS (reflected as % of baseline) during or after drug application. Each vertical bar represents PS amplitude ± SEM, and data were collected from 12 slices from 5 rats. The dotted line reflects the baseline (100%) control PS amplitude before drug treatment. Asterisks denote significant differences between control and treatment groups (*, <i>p</i> < 0.05; ** <i>p</i> < 0.01; ***, <i>p</i> < 0.001), whereas # indicates significant differences between the ketones plus H<sub>2</sub>O<sub>2</sub> group, and other groups in which pretreatment of ketones occurred before H<sub>2</sub>O<sub>2</sub> application (<i>p</i> < 0.05).</p>", "links"=>[], "tags"=>["KATP channel activation", "Hippocampal Synaptic Integrity", "KATP channel activator diazoxide", "KATP channels", "synaptic protection", "hippocampal synaptic protection", "hd", "exogenous oxidative stress", "kd", "ketone"], "article_id"=>1368882, "categories"=>["Biological Sciences"], "users"=>["Do Young Kim", "Mohammed G. Abdelwahab", "Soo Han Lee", "Derek O’Neill", "Roger J. Thompson", "Henry J. Duff", "Patrick G. Sullivan", "Jong M. Rho"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0119316.g001", "stats"=>{"downloads"=>7, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ketones_ameliorate_synaptic_impairment_caused_by_hydrogen_peroxide_H_2_O_2_/1368882", "title"=>"Ketones ameliorate synaptic impairment caused by hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-07 02:51:46"}

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  • {"unique-ip"=>"17", "full-text"=>"20", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"23", "full-text"=>"23", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"27", "full-text"=>"34", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"17", "full-text"=>"19", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"20", "full-text"=>"21", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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