Amelioration of popolysaccharide-induced sepsis in rats by free and esterified carnitine

The purpose of this study was to determine if free or esterified carnitine could alter fatty acid metabolism and ameliorate sepsis in lipopolysaccharide (LPS)-treated rats. Throughout a 96 h observation post-LPS, i.p. administration of both markedly reduced illness and accelerated recovery. Carnitine prevented the acute LPS-induced rise in serum triglycerides (45 ± 6, 59 ± 5 vs. 83 ± 8 mg/ml, p < 0.001), respectively. This difference was accompanied by a significant increase in liver lipogenesis in LPS controls compared to both carnitines and normal rats (6.1 ± 0.3 vs. 3.9 ± 0.5, 4.3 ± 0.5, and 1.8 ± 0.4 μmol/h, respectively, p < 0.04). Compared to normal rats, total liver carnitine was significantly elevated in LPS controls and even higher in the carnitine groups (357 ± 40 vs. 736 ± 38, 796 ± 79, and 1081 ± 21 nmol/g). The data suggest that carnitines may be of therapeutic value in sepsis treatment and one action may be to partition fatty acids from esterification to oxidation

mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

ObjectivesThere is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function.MethodsAdult male streptozotocin treated Spragueâ Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG).ResultsIn diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20â fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGCâ 1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons.InterpretationActivation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1â PGCâ 1αâ TFAM axis and preservation of mitochondrial OXPHOS function.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142324/1/acn3484.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142324/2/acn3484_am.pd

Dopamine release from canine striatum following global cerebral ischemia/reperfusion

The elevation of extracellular dopamine (DA) levels in the striatum of experimental animals subjected to ischemic insult has been well documented. The contribution of excessive DA to neuronal damage can be inferred from the ability of DA antagonist, as well as selective destruction of dopaminergic tracts, to confer neuroprotection in models of ischemia. In the current study, we report an enhanced releasability of preloaded [3H]DA in response to either elevated potassium or N-methyl-d-aspartate (NMDA) from striatal slices of beagles that had experienced 10 min of ischemia induced by cardiac arrest. The elevation in sensitivity to potassium stimulation was transient, approaching control levels after 30 min of reperfusion. In contrast, release stimulated by NMDA was elevated immediately after cardiac arrest and remained elevated for as long as 24 h of reperfusion. Release stimulated by NMDA was enhanced by glycine (Gly) and inhibited by MK801, consistent with mediation through the NMDA receptor/channel complex. The increased sensitivity of DA release, coupled with the high levels of excitatory amino acids (EAAs), including glutamate (Glu), aspartate (Asp) and Gly in ischemic brain, probably contribute to the extensive neuronal cell damage. © 1993

The role of L-type voltage dependent calcium channels in stimulated [\u3csup\u3e3\u3c/sup\u3eH]norepinephrine release from canine hippocampal slices following global cerebral ischemia and reperfusion

The hippocampus is among those brain regions which are selectively vulnerable to ischemic damage. Hippocampal damage due to transient cerebral ischemia is mainly of the delayed, non-necrotic type which may arise after disruption or activiation of specific cellular systems, including transmitter release through excitatory amino acid receptors. We investigated the contribution of L-type voltage dependent calcium channels (VDCCs) to glycine (GLY) potentiatedN-methyl-d-aspartate (NMDA) receptor- and potassium-stimulated [3H]norepinephrine (NE) release in a canine model of global cerebral ischemia and reperfusion. Tissue was collected from four experimental groups: non-arrested controls (NA), global cerebral ischemia induced by 10 minute cardiac arrest (CA), and CA followed by 30 min or 24 hours reperfusion after restoration of spontaneous circulation. Brain slices prepared from all groups accumulated approximately equivalent amounts of [3H]NE. The sensitivity of [3H]NE release to stimulation by NMDA/GLY or elevated potassium was unchanged after ischemia and reperfusion. About 30% of release stimulated by the addition of 20 mM potassium was inhibited by the NMDA receptor-operated channel antagonist MK801 in all groups except CA in which only 4% of release was inhibited by MK801. The ability of 1 μM nitrendipine (NTP) to block stimulated release indicated that the contribution of the L-type VDCC to potassium or NMDA/GLY-stimulated release was significant only in NA and 24 hour reperfused animals. These data suggest that NE release may be stimulated through the NMDA receptor channel at control levels for up to 24 hours after ischemic insult and that the L-type VDCC is not a significant mediator of Ca++-induced [3H]NE release in arrest and early reperfusion. The data also support the involvement of the L-type VDCC in regulating NMDA-stimulated release in NA and 24 hour reperfused animals. The results in hippocampus demonstrate a different pattern of L-type VDCC-mediated catecholamine release following ischemia and reperfusion from that found for [3H]dopamine release from canine striatal slices in our previous study. © 1995 Elsevier Science B.V. All rights reserved