(1) The incidence of cardiac arrest and neurologic injury related to regional anesthesia were very low, but both were more than three SDs greater after spinal anesthesia than after other regional procedures. (2) Two thirds of the patients with neurologic deficits had either a paresthesia during needle placement or pain on injection. (3) Seventy-five percent of the neurologic deficits after nontraumatic spinal anesthesia occurred in patients who had received hyperbaric lidocaine, 5%.
1 Clinical studies have shown enhancement of cyclosporine toxicity when co-administered with the immunosuppressant sirolimus. We evaluated the biochemical mechanisms underlying the sirolimus/ cyclosporine interaction on rat brain metabolism using magnetic resonance spectroscopy (MRS) and compared the e ects of sirolimus with those of the structurally related RAD. 2 Two-week-old rats (25 g) were allocated to the following treatment groups (all n=6): I. control, II. cyclosporine (10 mg kg 71 d 71 ), III. sirolimus (3 mg kg 71 d 71 ), IV. RAD (3 mg kg 71 d 71 ), V. cyclosporine+sirolimus and VI. cyclosporine+RAD. Drugs were administered by oral gavage for 6 days. Twelve hours after the last dose, metabolic changes were assessed in brain tissue extracts using multinuclear MRS. 3 Cyclosporine signi®cantly inhibited mitochondrial glucose metabolism (glutamate: 78+6% of control; GABA: 67+12%; NAD + : 76+3%; P50.05), but increased lactate production. Sirolimus and RAD inhibited cytosolic glucose metabolism via lactate production (sirolimus: 81+3% of control, RAD: 69+2%; P50.02). Sirolimus enhanced cyclosporine-induced inhibition of mitochondrial glucose metabolism (glutamate: 60+4%; GABA: 59+8%; NAD + : 45+5%; P50.02 versus cyclosporine alone). Lactate production was signi®cantly reduced. In contrast, RAD antagonized the e ects of cyclosporine (glutamate, GABA, and NAD + , not signi®cantly di erent from controls). 4 The results can partially be explained by pharmacokinetic interactions: co-administration increased the distribution of cyclosporine and sirolimus into brain tissue, while co-administration with RAD decreased cyclosporine brain tissue concentrations. In addition RAD, but not sirolimus, distributed into brain mitochondria. 5 The combination of cyclosporine/RAD compares favourably to cyclosporine/sirolimus in regards to their e ects on brain high-energy metabolism and tissue distribution in the rat.
EP enters cells, provides pyruvate as a tricarboxylic acid substrate, and is more protective. Although EP provides metabolic protection of adenosine triphosphate levels, it does not maximize antioxidant protection.
Previous neuron and glial cell culture studies of excessive poly (ADP-ribose) polymerase (PARP-1) activation found NAD + depletion, glycolytic arrest, and cell death that could be avoided by exogenous tricarboxylic acid cycle (TCA) metabolites, especially pyruvate (pyr). Pyruvate neuroprotection has been attributed to cytosolic NAD + replenishment, TCA metabolism, and antioxidant activity. We investigated the first two mechanisms in respiring cerebrocortical slices after a 1-h H 2 O 2 exposure to activate PARP-1. H 2 O 2 was followed by a 4-h recovery with oxy-artificial cerebrospinal fluid superfusion having either: (1) no glucose (glc) or pyruvate; (2) 10 mmol/L glc only; (3) 10 mmol/L pyruvate only; (4) both 10 mmol/L glc and 10 mmol/L pyruvate. Poly-ADPribosylation was quantified from Western blots and immunohistochemistry. Perchloric acid extracts were quantified with 14.1 T 31 P nuclear magnetic resonance spectroscopy. Just after H 2 O 2 exposure, ATP and NAD + decreased by E50%, PCr decreased by 75%, and the ADP/ATP ratio approximately doubled. ATP and NAD + changes, but not PCr changes, were nearly eliminated if PARP inhibitors accompanied the H 2 O 2 . Recovery with both pyruvate and glc was better than with glc alone, having higher ATP (0.161 versus 0.075, P < 0.01) and PCr levels (0.144 versus 0.078, P < 0.01), and higher viable cell counts in TUNEL and Fluoro-Jade B staining. Two-dimensional [ 1 H-13 C] HSQC spectra showed metabolism during recovery of 13 C glc or pyr. Pyruvate metabolism was primarily via pyruvate dehydrogenase, with some via pyruvate carboxylation. Pyruvate superfusion of PARPinjured brain slices helps replenish NAD + while providing metabolic fuel. Although this augments recovery, a strong antioxidant role for pyruvate has not been ruled out.
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