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Inhibition of the Kynurenine-NAD+ Pathway Leads to Energy Failure and Exacerbates Apoptosis in Pneumococcal Meningitis

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Inhibition of the Kynurenine-NAD+ Pathway Leads to Energy Failure and Exacerbates Apoptosis in Pneumococcal Meningitis J Neuropathol Exp Neurol Vol. 69, No. 11 Copyright Ó 2010 by the American Association of Neuropathologists, Inc. November 2010 pp. 1096Y1104 ORIGINAL ARTICLE Inhibition of the Kynurenine-NAD+ Pathway Leads to Energy Failure and Exacerbates Apoptosis in Pneumococcal Meningitis Caroline L. Bellac, PhD, Roney S. Coimbra, PhD, Stephan Christen, PhD, and Stephen L. Leib, MD Downloaded from https://academic.oup.com/jnen/article/69/11/1096/2917121 by guest on 28 September 2021 We previously showed that in experimental pneumo- Abstract coccal meningitis, the kynurenine (KYN) pathway is acti- Pneumococcal meningitis causes neurological sequelae, including vated, and that this leads to accumulation of KYN metabolites learning and memory deficits in up to half of the survivors. In both in the hippocampus (11). Activation of the KYN pathway humans and in animal models of the disease, there is apoptotic cell and the resulting increase in KYN intermediates have been death in the hippocampus, a brain region involved in learning and documented in other neuroinflammatory diseases and in neuro- memory function. We previously demonstrated that in an infant rat degenerative diseases (12Y14). The pathogenesis of brain in- model of pneumococcal meningitis, there is activation of the kynuren- jury in these disorders may involve the accumulation of ine (KYN) pathway in the hippocampus, and that there was a positive KYN metabolites such as 3-hydroxykynurenine (3-HKYN), correlation between the concentration of 3-hydroxykynurenine and the 3-hydroxyanthranilic acid (3-HAA), or quinolinic acid extent of hippocampal apoptosis. To clarify the role of the KYN path- (QUINA) (15Y17). We also found that 3-HKYN concentra- way in the pathogenesis of hippocampal apoptosis in pneumococcal tions in pneumococcal meningitis correlated to the extent of meningitis, we specifically inhibited 2 key enzymes of the KYN path- hippocampal apoptotic damage (11). Moreover, 2 recent stud- way and assessed hippocampal apoptosis, KYN pathway metabolites, ies of parasitic brain infections (African trypanosomiasis and and nicotinamide adenine dinucleotide (NAD) concentrations by high- cerebral malaria) in mice showed that inhibition of the KYN performance liquid chromatography. Pharmacological inhibition of kyn- pathway by Ro-61-8048 reduced brain inflammation and pro- urenine 3-hydroxylase and kynureninase led to decreased cellular NAD+ longed survival, suggesting that KYN pathway inhibition may levels and increased apoptosis in the hippocampus. The cerebrospi- represent a therapeutic option in neuroinflammatory diseases nal fluid levels of tumor necrosis factor and interleukin-1> and -A (18, 19). were not affected. Our data suggest that activation of the KYN path- The KYN pathway is the major route of tryptophan way in pneumococcal meningitis is neuroprotective by compensating catabolism and the only de novo synthesis pathway of the for an increased NAD+ demand caused by infection and inflamma- essential coenzyme nicotinamide adenine dinucleotide tion; this mechanism may prevent energy failure and apoptosis in the (NAD) (Fig. 1). Activation of the KYN pathway has been hippocampus. reported to counteract NAD+ depletion in activated macro- phages and astrocytes (12, 20). The NAD+ is an essential Key Words: Apoptosis, Energy failure, Hippocampus, Kynurenine, cofactor in various cellular reactions, including adenosine Meningitis, Pharmacological inhibition, Streptococcus pneumoniae. triphosphate synthesis and DNA repair. Intracellular NAD+ and adenosine triphosphate levels are known to be critical for cell survival (21, 22). Although NAD+ can be recycled from INTRODUCTION nicotinic acid or nicotinamide, de novo synthesis of NAD+ Pneumococcal meningitis is associated with a mortality occurs by the KYN pathway. rate of up to 30% and persistent neurological sequelae in up Here, we assessed the role of KYN pathway activation to 50% of survivors because of different degrees and extents in hippocampal apoptosis by pharmacological inhibition of of brain damage (1, 2). Apoptosis of hippocampal neurons the pathway at the level of kynurenine 3-hydroxylase (HK) occurs in pneumococcal meningitis in humans and is asso- and kynureninase (KZ) in an infant rat model of pneumo- ciated with learning and memory deficits in corresponding coccal meningitis. animal models of the disease (3Y7). Both the pathogen and the host inflammatory reaction may contribute to the development MATERIALS AND METHODS of hippocampal neuronal injury (1, 8Y10). Materials Tryptophan, KYN, 3-HKYN, kynurenic acid (KYNA), From the Institute for Infectious Diseases, University of Bern, Bern, Switzerland. magnesium chloride hexahydrate, bathophenanthroline disul- Send correspondence and reprint requests to: Stephen L. Leib, MD, Institute fonic acid, and the oxidized and reduced forms of NAD (NAD+/ for Infectious Diseases, University of Bern, Friedbuehlstrasse 51, P.O. NADH) were obtained from Sigma (St Louis, MO). An- Box 61, CH-3010 Bern, Switzerland; E-mail: [email protected] This work was supported by grants 31-120725 and 31-116257 from the Swiss thranilic acid (AA), zinc acetate dihydrate, TRIS hydrochlo- National Science Foundation and by Grant mkl/stm 55-2005 from the ride, ammonium acetate, tetrabutylammonium hydrogen sulfate Roche Research Foundation. and perchloric acid were from Fluka (Buchs, Switzerland). 1096 J Neuropathol Exp Neurol Volume 69, Number 11, November 2010 Copyright © 2010 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. J Neuropathol Exp Neurol Volume 69, Number 11, November 2010 Kynurenine-NAD+ Pathway in Pneumococcal Meningitis animals (n = 24) were injected with 10 KL of sterile saline solution. At 18 hours after injection of bacteria or saline, the animals were clinically assessed by scoring disease se- verity (1 = coma; 2 = does not turn upright; 3 = turns upright within 30 seconds; 4 = minimal ambulatory activity, turns upright in less than 5 seconds; and 5 = normal). Cerebrospinal fluid (CSF) was obtained by puncture of the cisterna magna, and 5 KL was serially diluted and cultured to determine bacterial CSF titers (24). All animals then received antibi- otic therapy (ceftriaxone, 100 mg/kg subcutaneously; Roche Pharma, Reinach, Switzerland) and were killed at prede- termined time points (i.e. at 24 hours or 36 hours after infection) by an overdose of intraperitoneally injected pento- Downloaded from https://academic.oup.com/jnen/article/69/11/1096/2917121 by guest on 28 September 2021 barbital (150 mg/kg). Immediately after death, the animals were perfused with 30 mL of ice-cold PBS via the left cardiac ventricle. Animal studies were approved by the Animal Care and Experimentation Committee of the Canton Bern, Switzerland and followed the National Institutes of Health’s guidelines for the performance of animal experiments. Pharmacological Inhibition of the KYN Pathway by Ro-61-8048 and oMBA To test the contribution of 3-HKYN on neuronal apop- tosis, we administered the specific HK inhibitor Ro-61-8048. Preliminary dose-finding tests directed us to use 75 mg/kg, intraperitoneally injected at 8 hours, 16 hours, 24 hours, and 32 hours after infection. In contrast to humans, who synthesize 3-HAA exclu- sively from 3-HKYN, rats synthesize 3-HAA also from an FIGURE 1. Schematic of the kynurenine pathway, the de novo intermediate metabolite AA, albeit to a lesser degree (Fig. 1). synthesis pathway of nicotinamide adenine dinucleotide To assess whether potentially neurotoxic metabolites further (NAD+). Tryptophan (TRP) is metabolized over different meta- downstream of 3-HKYN (e.g. 3-HAA and QUINA) contrib- bolic steps into quinolinic acid (QUINA) and culminates with ute to apoptosis, we inhibited the enzyme KZ by administer- + the formation of NAD . Different points for pharmacological ing oMBA in parallel. This was done by administration of intervention are indicated (gray shaded ovals). The compound 75 mg/kg Ro-61-8048 and 50 mg/kg oMBA intraperitoneally Ro-61-8048 inhibits the transformation of kynurenine into 3- at 8 hours, 16 hours, 24 hours, and 32 hours after infection. hydroxykynurenine (3-HKYN) by blocking the enzyme kyn- urenine 3-hydroxylase (HK). The activity of kynureninase (KZ) Vehicle solution consisted of aqua ad injectabilia with 0.1% is decreased by the inhibitor of kynureninase (oMBA), resulting Tween 80. in lower levels of anthranilic acid (AA) and 3-hydroxyanthranilic For quantification of CSF cytokine levels and determi- + acid (3-HAA). HAD, anthranilate 3-monooxygenase; IDO, in- nation of hippocampal NAD levels, animals were killed at doleamine 2,3-dioxygenase; KAT, kynurenine aminotransfer- 24 hours after infection. For evaluation of hippocampal ase; KYNA, kynurenic acid. apoptosis in 1 hemisphere and determination of hippocampal KYN metabolites in the other hemisphere, animals were killed Acetonitrile, methanol, potassium cyanide, and all other re- at 36 hours after infection. These time points were based on agents were of high-performance liquid chromatography our previous demonstration that apoptotic damage peaks at (HPLC) grade and purchased from Merck (Darmstadt, Ger- approximately 36 hours after infection (25). Because the pathophysiological events leading to apoptosis precede the many). Analytical-grade water was prepared using a Milli-Q + synthesis purification system (Millipore, Zug, Switzerland). All histological appearance of apoptosis, we measured NAD mobile phases were filtered through 0.22-KmDuraporemem-
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