Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats

Pharmacological Reports 66 (2014) 1134–1139

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Original research article

Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats Iwona Chmiel-Perzyn´ska a, Adam Perzyn´ski a, Ewa M. Urban´ska a,b,* a b

Medical University of Lublin, Lublin, Poland Institute of Agricultural Medicine, Lublin, Poland

A R T I C L E I N F O

Article history: Received 3 July 2014 Received in revised form 24 July 2014 Accepted 28 July 2014 Available online 10 August 2014 Keywords: Diabetes mellitus type 1 Kynurenic acid Memory Neurodegeneration

A B S T R A C T

Background: Diabetes mellitus (DM) is frequently associated with peripheral and central complications and has recently emerged as a risk factor for cognitive impairment and dementia. Kynurenic acid (KYNA), a unique tryptophan derivative, displays pleiotropic effects including blockade of ionotropic glutamate and a7 nicotinic receptors. Here, the influence of experimental diabetes on KYNA synthesis was studied in rat brain. Methods: DM was induced by i.p. administration of streptozotocin (STZ). Five weeks later, KYNA content and the activity of semi-purified kynurenine aminotransferases (KATs) were measured in frontal cortex, hippocampus and striatum of diabetic and insulin-treated rats, using HPLC-based methods. Results: Hippocampal but not cortical or striatal KYNA concentration was considerably increased during DM, either untreated or treated with insulin (220% and 170% of CTR, respectively). The activity of kynurenine aminotransferase I (KAT I) was not affected by DM in all of the studied structures. KAT II activity was moderately increased in cortex (145% of CTR) and hippocampus (126% of CTR), but not in striatum of diabetic animals. Insulin treatment normalized cortical but not hippocampal KAT II activity. Conclusions: A novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, however, it may also have negative impact on cognition. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Introduction The prevalence of diabetes mellitus (DM) is rapidly increasing in modern societies and currently affects 5–7% of the population worldwide [1,2]. The concept of diabetes has widened during past decades due to recognition of its broad range and several mechanisms involved in pathogenesis. With hyperglycemia as a common feature, diabetes is currently categorized into four major types: DM type 1, DM type 2, other types of DM and gestational

Abbreviations: AMPA, a-amino-isoxazolepropionate; CNS, central nervous system; DM, diabetes mellitus; ERK 1/2, extracellular signal-regulated kinases; GFAP, glial fibrillary acidic protein; GSK-3b, glycogen synthase kinase-3b; HPLC, high pressure liquid chromatography; IDO, indoleamine 2,3-dioxygenase; INS, insulin; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYNA, kynurenic acid; NMDA, N-methyl-D-aspartate; STZ, streptozotocin. * Corresponding author. E-mail address: [email protected] (E.M. Urban´ska).

diabetes. Insufficient production or compromised action of insulin leads to increased blood glucose level and triggers complex panel of metabolic disturbances, accompanied by inflammation, oxidative stress and vascular damage [2,3]. Adequate control of disease with the use of insulin and novel oral hypoglycemic agents is nowadays easier to achieve. However, at the later stage of disorder, various complications frequently affect multiple tissues and organs, including central and peripheral nervous system [3]. DM frequently coincides with depression and has been associated with higher risk of dementia and cognitive decline, however, the underlying mechanisms remain poorly defined and seem to be multifactorial [4–6]. Emerging data suggest the involvement of glucose toxicity, insulin resistance, mitochondrial dysfunction, inflammatory processes or impaired neurogenesis [4,5]. Furthermore, a number of abnormalities in neurotransmitter systems including glutamate-mediated transmission have been linked with diabetic deficit of cognition [7]. Cortical and hippocampal alterations in glutamate level and disturbed expression and

http://dx.doi.org/10.1016/j.pharep.2014.07.014 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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functioning of N-methyl-D-aspartate (NMDA) and a -aminoisoxazolepropionate (AMPA) receptors were reported in animals with experimentally induced DM [8–11]. Kynurenic acid (KYNA) is a unique endogenous tryptophan derivative with pleiotropic activities [12,13]. Initially recognized as a broad-spectrum endogenous antagonist of ionotropic glutamate receptors, KYNA was later discovered to target also a7 nicotinic receptors, and to act as a G protein-coupled GPR35 receptor ligand and an agonist of human aryl hydrocarbon receptors [13,14]. In the brain, KYNA is formed primarily within glial cells along kynurenine pathway, in the reaction catalyzed by kynurenine aminotransferases (KATs) I-IV converting its immediate precursor, L-kynurenine [14,15]. Among tryptophan metabolites, only KYNA displays neuroprotective properties; therefore its deficiency was implicated in the development of neuronal loss under pathological conditions [12,13]. On the other hand, increased KYNA levels, via blockade of glutamate-mediated neurotransmission may exert negative impact on memory and cognitive processes [16]. We have previously shown that production of KYNA is stimulated in cortical slices and glial cultures under conditions resembling hyperglycemic ketosis and by ketone body, b-hydroxybutyrate, in a protein kinase A-dependent way [17]. The aim of this study was to assess the effect of experimental DM type 1, untreated or treated with insulin, on KYNA levels and the activity of its biosynthetic enzymes, KAT I and II in vivo, in rat brain.

Experimental procedure Animals Experiments were performed on male Wistar rats (220–250 g). Animals were housed under standard laboratory conditions (20 8C environmental temperature; food and water available ad libitum). Experimental procedures have been approved by the Local Ethical Committee in Lublin and are in agreement with European Communities Council Directive on the use of animals in experimental studies. Diabetes mellitus (DM) DM type 1 was induced by single administration of streptozotocin (STZ), in the dose of 60 mg/kg i.p, diluted in 0.05 M citrate buffer, pH 4.2. The injection volume was 1 ml/100 g of animal body weight. Experimental groups included 12 animals each. Glucosuria, confirmed by semiquantitative method using Ketodiastix (Bayer) test straps one week after injection of STZ, was the criterion of diagnosing DM. Administration of insulin was started after confirmation of glucosuria. NPH insulin was given sc once daily, in the substitution dose of 9 IU/kg [18], sufficient to prevent glucosuria. DM group received 0.9% NaCl instead of insulin. Control group (CTR) was given appropriate volume of 0.05 M citrate buffer instead of STZ and, subsequently, injected daily with 0.9% NaCl. Treatment was conducted for four weeks. Diabetic animals (DM and DM + INS) were monitored daily for body weight and urine glucose. Substances STZ and L-kynurenine sulphate salt were obtained from Sigma– Aldrich (St. Louis, USA). NPH insulin (Gensulin N) was received from Bioton and 0.9% NaCl was acquired from Polpharma. All the high pressure liquid chromatography (HPLC) reagents were purchased from J.T. Baker Laboratory Chemicals (Holland). Other reagents were obtained from POCH (Gliwice, Poland).

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KYNA levels in the brain structures 35 days after administration of STZ, rats were decapitated and their brains were quickly removed from the skull. Hippocampi, striata, and frontal cortices were quickly dissected on ice and stored separately (72 8C) until further analyses. On the day of analysis, randomly chosen single tissue structures from either right or left hemisphere were homogenized 1:10 (weight/volume) in distilled water (Bandelin Sonopuls, Germany), at ice-cold bath (4 8C). The obtained homogenate was centrifuged (13,600  RCF, 5 min, 4 8C), acidified with 0.1 ml of 1 N HCl and 14 ml of 50% trichloroacetic acid and centrifuged again (conditions as above). Supernatants were applied to the cation-exchange columns (Dowex 50 W, H+ form), which were prewashed with 1 ml of water and 1 ml of 0.1 N HCl. Columns were subsequently washed with 1 ml of 0.1 N HCl and 1 ml of water. KYNA was eluted with 2.5 ml of water. Determination of activity of kynurenine aminotransferases I and II (KAT I and II) KAT I and KAT II activities were assayed with a method described by Guidetti et al. [15]. Briefly, rats cortices, hippocampi and striata were homogenized 1:10 (weight:volume) in dialysis buffer (40 ml of Tris–acetate buffer, pH 8.0, 40 mg of pyridoxal-50 phosphate, 3.12 ml of 2-mercaptoethanol, 3960 ml of distilled water). Homogenate was centrifuged (13,600  RCF, 10 min, +4 8C). Supernatants were placed separately in cellulose membranes (Dialysis tubing, Sigma) and dialyzed against 4 l of dialyzing buffer (composed as above) for 15 h, at 4 8C. The dialyzates (100 ml) were incubated (37 8C, 20 h) in the reaction mixture containing (final concentrations): 2 mM L-kynurenine, 1 mM pyruvate, 70 mM pyridoxal-50 -phosphate, 150 mM Tris–acetate buffer, pH 7.0 or 9.5, for KAT II or KAT I, respectively. Glutamine (2 mM), the inhibitor of KAT I, was added to samples assayed for KAT II activity. After incubation, samples were rapidly chilled to 4 8C, acidified with 1 ml of 0.1 N HCl and 14 ml of 50% trichloroacetic acid, and centrifuged (13,600  RCF, 5 min, +4 8C). The obtained supernatants were treated as described above. Blank samples were prepared from heat-inactivated dialysate (98 8C, 15 min). Quantification of KYNA Eluted KYNA was subjected to the HPLC and quantified fluorimetrically (Varian HPLC system; ESA catecholamine HR80.3 mm, C18 reverse-phase column), as previously described [19]. The mobile phase (pH 6.2) contained 250 mM zinc acetate, 50 mM sodium acetate and 4% acetonitrile. Retention time of KYNA was 4.5–5.0 min with 1 ml/min mobile phase flow. Each chromatographic assay was preceded by the measurements of standardized concentrations of KYNA (0.2, 0.4, 0.6, 0.8 and 1.0 pmol) in order to obtain calibration curve. Statistical analyses The statistical analyses were performed using one-way analysis of variance (ANOVA test), with the adjustment of p value by the Bonferroni method. Data are presented as the mean values  SD.

Results Serum glucose level reached 176 mg/dl (123% of CTR; ns) in DM + INS group and 585 mg/dl (409% of CTR; p < 0.001) in DM group.

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Cortical KYNA level was not altered by DM or DM + INS in comparison with CTR (17.54  2.61 and 16.73  3.68 vs 17.61  3.36 fmol of KYNA/mg of tissue, respectively) (Fig. 1A). DM and DM + INS increased hippocampal KYNA content (10.35  2.5 and 7.92  1.48 vs 4.66  0.81 fmol KYNA/mg of tissue, respectively), to 222% of CTR (p < 0.001) and 170% of CTR (p < 0.05), respectively (Fig. 1B). Striatal level of KYNA was not affected by DM or DM + INS (15.62  2.61 and 15.04  3.01 vs 14.6  3.51 fmol KYNA/mg of tissue, respectively) (Fig. 1C). The activity of KAT I in cerebral cortices did not differ among DM, DM + INS and CTR groups (1.26  0.21 and 1.13  0.11 vs 1.17  0.17 pmol KYNA/mg of tissue/h, respectively) (Fig. 2A). Hippocampal KAT I activity was not altered by DM or DM + INS, as compared with CTR (0.58  0.08 and 0.58  0.1 vs 0.57  0.1 pmol KYNA/mg of tissue/h, respectively) (Fig. 2C). DM and DM + INS did not influence the striatal activity of KAT I, in comparison with CTR

CORTEX A KYNA level (fmol/mg of ssue)

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Fig. 1. The effect of experimental diabetes on KYNA levels in frontal cortex, hippocampus and striatum. The experimental groups included: (a) DM – animals with experimental diabetes induced by streptozotocin (STZ), (b) DM + INS – animals with diabetes, treated daily with insulin, and (c) CTR – control animals that received solvent instead of STZ and daily injections of 0.9% NaCl. N = 12 animals for each group. Values are the mean  SD; *p < 0.05, ***p < 0.001 vs control (ANOVA with the adjustment of p value using Bonferroni method).

(0.56  0.073 and 0.53  0.08 vs 0.52  0.06 pmol KYNA/mg of tissue/h, respectively) (Fig. 2E). DM but not DM + INS increased cortical KAT II activity to 145.5% (p < 0.01) of CTR (0.97  0.09 and 0.72  0.12 vs 0.67  0.14 pmol KYNA/mg of tissue/h, respectively) (Fig. 2B). Hippocampal KAT II activity was increased in DM and DM + INS groups to 131.6% and 126.3% of control (0.25  0.03 and 0.24  0.04 vs 0.19  0.03 pmol KYNA/mg tissue/h, respectively; both p < 0.01) (Fig. 2D). Striatal KAT II activity was not changed by DM or DM + INS (0.31  0.05 and 0.3  0.07 vs 0.27  0.06 pmol KYNA/mg of tissue/h, respectively) (Fig. 2F). Discussion Our data reveal novel aspect of DM-related hippocampal abnormalities. Experimental DM, either untreated or treated with insulin, prominently increased hippocampal, but not cortical or striatal KYNA level in rat brain. The activity of KAT I was not altered in the brain of diabetic rats, whereas the activity of KAT II was moderately higher in frontal cortex and to a minor degree in hippocampus. Insulin treatment prevented cortical, but not hippocampal rise of KAT II activity. In the brain, KYNA originates from the conversion of L-kynurenine carried out by KATs mainly within glial cells [13]. Proliferation of astrocytes in hippocampus of animals with experimentally-induced DM, possibly secondary to neuronal damage, and changes in the expression of glial proteins are well substantiated. An increase of glial fibrillary acidic protein (GFAP) level is the most frequent finding following 4–8 weeks of diabetes [20–23], although reductions of GFAP in hippocampus and cortex were also demonstrated [24–26]. Presented here results support the notion that DM changes the function of glial cells, as reflected by the hippocampal rise of KYNA and increased activity of KAT II in cortex and hippocampus. Distinct, structure-dependent responses of brain KYNA and KATs to DM seem to represent pathology specific for diabetes. Increased synthesis of KYNA in the course of DM could be associated with an enhanced ketone body formation. We have recently shown that in cortical slices and glial cultures main human ketone body, b-hydroxybutyrate, augments KYNA production by stimulating KATs activity in the protein kinase A-dependent way [17]. Raised KYNA synthesis was also evident under conditions resembling diabetic ketoacidosis [17]. In here, consistently higher KYNA levels and minor increases of hippocampal KAT II activity were apparent regardless of insulin therapy, which brought glucose levels to normal range and prevented ketoacidosis. On the contrary, cortical increase of KAT II activity was reversed by treatment with insulin. Thus, observed changes might result from the direct and rapid effect of ketosis on cortical but not hippocampal KAT II. In hippocampus, structure highly sensitive toward various insults, impairment of glial function and neuronal loss develop quite rapidly and become evident early after STZ injection [26]. Thus, in our paradigm, insulin therapy could have been introduced at the moment when diabetic complications were already triggered and reached irreversible phase in hippocampus. Increased KYNA level would persist, as indeed was the case. Such setting holds close resemblance to clinical picture. Due to relatively discrete initial symptoms, the diagnosis and therapy of DM usually come with a delay, yet effective therapy quickly restores proper glucose metabolism. However, with a progress of disease and despite the treatment, the occurrence of CNS complications steadily increases [3]. It is not fully clear, why more than double increase of hippocampal KYNA level did not correlate with the minor increase of KAT II activity and the increase of cortical KAT II activity was not paralleled by the rise of KYNA. The measurement

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B

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Corcal acvity of KAT II (pmol KYNA/mg of ssue/h)

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Fig. 2. The effect of experimental diabetes on the activity of kynurenine aminotransferases (KATs) I and II in frontal cortex (A, B), hippocampus (C, D) and striatum (E, F). The experimental groups included: (a) DM – animals with experimental diabetes induced by streptozotocin (STZ), (b) DM + INS – animals with diabetes, treated daily with insulin, and (c) CTR – control animals that received solvent instead of STZ and daily injections of 0.9% NaCl. N = 12 animals for each group. Values are the mean  SD; *p < 0.05, **p < 0.01, ***p < 0.001 vs control; ap < 0.05 vs DM (ANOVA with the adjustment of p value using Bonferroni method).

of KATs in semi-purified homogenate is reflecting the tissue expression of protein and does not allow the assessment of local intra- and extracellular milieu affecting the enzymatic activity. Although KAT II is generally believed to be a major enzyme contributing to KYNA formation, it is conceivable that even when its activity is increased, KYNA synthesis may be unchanged, e.g. due to the presence of enzymatic inhibitors. In fact, the lack of correlation between KYNA level and the activity of KAT II is not an unprecedented observation and was demonstrated before [27–29]. Various mechanisms may account for this phenomenon, including, for example, regional differences in relative contribution of KAT II versus other KATs to KYNA synthesis. However, up to our knowledge, the proportional involvement of distinct KAT enzymes (I–IV) in KYNA formation within specific brain structures

was not the subject of research. Secondly, unchanged KYNA concentration in cortex, despite increased KAT II activity, may reflect faster elimination of the compound from this brain area. Under physiological conditions, KYNA poorly penetrates into CNS [30]. Nevertheless, considering that the permeability of blood– brain barrier increases in diabetes and capillary vessels dysfunction varies among brain structures [31,32], such DM-related impairment of blood–brain barrier integrity could provide the base for faster cortical elimination of KYNA. In turn, KYNA level would be normalized, despite potential increase of its synthesis associated with an enhanced KAT II activity. Finally, the regional production of KYNA may be indirectly influenced by the availability of L-kynurenine and the activity of other enzymes along kynurenine pathway. The level of KYNA

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immediate precursor can be regulated by the relative activity of (a) indoleamine 2,3-dioxygenase (IDO), step-limiting enzyme catabolizing tryptophan to L-kynurenine and (b) kynurenine 3-monooxygenase (KMO), converting L-kynurenine to 3-OH-kynurenine. Compelling evidence suggests that various factors of exogenous and endogenous origin may affect KAT, IDO and KMO activity, with subsequent changes in KYNA production [14,28]. In fact, an increase of L-kynurenine levels was observed in hepatocytes from diabetic rats [33], and altered activity of various kynurenine pathway enzymes, including IDO, was detected in liver, kidneys and intestines of diabetic rabbits [34]. Interestingly, the direction of changes varied between different areas suggestive of separate, organ-specific regulation of kynurenine pathway [34]. Further studies should be aimed to assess the activity of IDO and KMO in diabetic brain and their relative contribution to the observed increase in KYNA formation. Apart from glial changes, a range of structural and functional alterations were reported in diabetic hippocampus [7,22]. Available data indicate the presence of modified expression and trafficking of several synaptic proteins, disturbed expression of early gene products (Fos and Jun) or reduced neurogenesis [22,24,35,36]. Among various neurotransmitter systems affected in DM, glutamate-mediated transmission seems to be of a special interest because of its dual role in the brain [7]. Glutamatergic system is crucial for neuronal communication as well as for learning and memory processes, however, when excessively active, easily triggers neuronal loss. Altered extracellular glutamate level and changes in number and function of glutamate receptors were frequently reported in DM. Although not fully consistent, majority of data suggest the link between late deficiency of hippocampal glutamate-mediated neurotransmission and cognitive impairment in diabetes, in contrast to early excessive activation of glutamate receptors, which may contribute to hippocampal neurodegeneration [7–10,37]. During late stage of disease, either minor increase or decrease of glutamate level were detected in rat hippocampus [38,39]. In diabetic mice, transient initial rise of hippocampal glutamate level followed by the later decrease, as well as an early enhancement of 3H-glutamate binding were reported [40]. In contrast, reduced binding to AMPA receptors, diminished expression of NR2B subunit and its phosphorylation and reduced NMDA currents in hippocampal pyramidal were described in chronic phase of DM in rats [8,10,11,40]. Presented here data are in line with earlier reports revealing increased formation of KYNA in human and experimentally induced diabetic cataractous lenses and aqueous humor [41,42]. Interestingly, increased brain KYNA production was also detected in experimental model of hepatic encephalopathy [43,44]. Our observations suggest the presence of regionally specific elevation of KYNA within the brain and further support the concept of impaired glutamate-mediated transmission in the course of DM. Despite earlier controversies, it is assumed now that even small local increases of brain KYNA may act presynaptically to inhibit glutamate release [45,46]. Behavioral studies in rats have demonstrated that higher cortical KYNA levels may affect certain aspects of memory and learning [16]. The abnormal synaptic plasticity, including impaired expression of long term potentiation and long term depression, was commonly described in experimental animals and in patients suffering from DM [7,11,47]. Cognitive dysfunction is perceived, at least partially, as a result of reduced glutamatemediated neurotransmission in hippocampus [7]. Hence, augmented synthesis of KYNA, initially aimed to restrict neuronal loss, may in turn exert undesirable effects on cognition and be associated with some symptoms of diabetic encephalopathy. The obtained data further support the concept of prominent role exerted by insulin within the CNS [48]. Brain insulin levels

appear to be 10–100 folds higher than in periphery, and insulin receptors (IRs) are widespread in the brain, including hippocampus and cerebral cortex [48,49]. Upon binding with IRs, insulin activates two major signaling pathways, the PI3K/Akt/glycogen synthase kinase-3b (GSK-3b) and the Ras/Raf-1/extracellular signal-regulated kinases (ERK1/2), involved in regulation of glucose homeostasis, antioxidant defense, neuronal growth and modulation of neurotransmission [48,49]. In here, insulin reversed the DM-related increase of cortical, but not of hippocampal KAT II activity suggesting that Akt/GSK-3b or Ras/Raf-1/ERK pathways might be involved in local regulation of KYNA synthesis. Future research should elucidate this issue. In summary, a novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, but it may also contribute to the cognitive impairment associated with progression of DM. Further studies, aimed to clarify the potential role of increased hippocampal KYNA formation in central complications of diabetes, must await new pharmacological tools able to target KYNA synthesis selectively, in distinct areas of CNS. Conflict of interest None. Acknowledgment This study was supported by the grants from Medical University of Lublin: DS 450/08, 450/13, 450/14.

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