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Complement C5a exhibits anxiolytic-like activity via the prostaglandin D2−DP1 receptor system coupled to adenosine A2A and GABAA receptors
Prostaglandins & other Lipid Mediators 98 (2012) 17–22
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Prostaglandins and Other Lipid Mediators
Complement C5a exhibits anxiolytic-like activity via the prostaglandin D2 −DP1 receptor system coupled to adenosine A2A and GABAA receptors Chihiro Miyamoto a,b , Mariko Yoshida a,b , Masaaki Yoshikawa a,b , Takafumi Mizushige a,c , Kousaku Ohinata a,b,∗ a
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 322-0012, Japan c Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto 606-8501, Japan b
a r t i c l e
i n f o
Article history: Received 25 January 2012 Received in revised form 27 March 2012 Accepted 30 March 2012 Available online 6 April 2012 Keywords: Anxiolytic activity Complement C5a Prostaglandin D2 DP1 receptor Adenosine A2A receptor GABAA receptor
a b s t r a c t We have recently found that central PGD2 exhibits anxiolytic-like activity. Here we show that complement C5a exhibits anxiolytic-like activity via the PGD2 system. Centrally administered C5a had anxiolytic-like activity at a dose of 0.3 pmol/mouse in the elevated plus-maze test in mice. C5a-induced anxiolytic-like activity was inhibited by indomethacin, a cyclooxygenase inhibitor, or BWA868C, an antagonist of DP1 receptor for PGD2 , respectively. The anxiolytic effect of C5a was also blocked by SCH58261 or bicuculline, antagonists of adenosine A2A and GABAA receptors, respectively, which were activated downstream of PGD2 –DP1 receptor. These results suggest that C5a exhibits anxiolytic-like activity via the PGD2 –DP1 receptor system coupled to the activation of adenosine A2A and GABAA receptors.
1. Introduction Prostaglandin (PG) D2 is the most abundant PG produced in the central nervous system (CNS) [1] and is involved in various central actions, including sleep induction, anxiolytic-like activity, hypothermia and attenuation of the pain response [2–7]. PGD2 is produced endogenously from arachidonic acid, via PGH2 , by lipocalin-type PGD synthase (L-PGDS), which is located in the arachnoid membrane and choroid plexus of the brain [8,9]. DP1 receptor selective for PGD2 has been isolated and characterized as a seven-transmembrane Gs protein-coupled rhodopsin-type receptor [10] In situ hybridization and immunohistochemistry assays with mice have revealed that the DP1 receptor is present in the arachnoid membrane in the basal forebrain [11,12]. We have recently reported that centrally administrated PGD2 stimulates food intake and exhibits anxiolytic-like activity via the DP1 receptor, and both L-PGDS- and DP1 -like immunoreactivity was detected in the hypothalamus, an important site for regulation of food intake
∗ Corresponding author at: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan. Tel.: +81 774 38 3733, fax: +81 774 38 3774. E-mail address: [email protected] (K. Ohinata). 1098-8823/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prostaglandins.2012.03.004
© 2012 Elsevier Inc. All rights reserved.
and emotional behavior [6,7]. The anxiolytic-like activity of PGD2 was mediated via activating the adenosine A2A and GABAA receptors. In addition, we have found that PGE2 , a structure isomer of PGD2 , exhibits anxiolytic-like activity in a manner dependent on the serotonin 5-HT1A , dopamine D1 and GABAA receptors, downstream of the EP1 /EP4 receptors [13]. The complement system, a series of proteins activated in response to pathogen invasion, plays an important role in the peripheral immune system [14]. Complement C5a is a 74-amino acid polypeptide derived from C5 by enzymatic degradation during activation of the complement system [14]. C5a has a variety of physiological activities, such as stimulation of histamine secretion in mast cells, increased capillary vessel permeability, contraction of smooth muscle, chemotaxic activity, and facilitation of phagocyte mobilization [14]. C5a is also called anaphylatoxin, since it induces anaphylactic-like reaction after peripheral administration. It has been revealed that the complement system, including C5a and its receptor, is present in the CNS as well as the peripheral immune system [15]. We have also found that C5a stimulates food intake after central administration via the PGD2 system [16], which is associated with emotional behavior [7]. Thus, we investigated whether centrally administrated C5a exhibits anxiolytic activity, and the mechanism underlying its activity.
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2. Materials and methods 2.1. Materials Human complement C5a was purchased from Sigma Chemical Co. (St. Louis, MO); and DP1 receptor-antagonist BWA868C was from Cayman Chemical (Ann Arbor, MI). SCH58261, an adenosine A2A receptor antagonist; and bicuculline, a ␥-aminobutyric acid type A (GABAA ) antagonist; were obtained from Tocris Bioscience (Bristol, UK). C5a-desArg was purchased from Calbiochem (Darmstadt, Germany) 2.2. Animals Four-week-old male ddY mice, 20–24 g body weight, for intracerebroventricular (i.c.v.) administration, respectively, were obtained from SLC (Shizuoka, Japan). This ddY strain, a closed colony with a rapid growth rate and high reproductive potential, has frequently been used in various biomedical researches, including behavioral pharmacological tests, as previously described [17–21]. All animals were housed in a temperature-controlled room (23 ◦ C) on a 12 hr light–dark cycle with lights on at 07:00. All animals had free access to food pellets and water. All experiments were approved by Kyoto University Ethics Committee for Animal Research Use. All animals were euthanized by an overdose of anesthesia drugs after the experiment. 2.3. Elevated plus-maze test Anxiolytic-like behavior was measured using the elevated plusmaze (EPM) test, which was performed as described previously [17–20]. Four arms (25 cm long × 5 cm wide) were placed 50 cm above the ground. Two opposite arms were delimited by acrylic vertical walls (15 cm high, closed arms), whereas the other two, opposite arms had unprotected edges (open arms). A mouse was placed in the center of the maze facing an open arm and observed for 5 min to measure the cumulative time and frequency of entries into open and closed arms. Arm entry was defined as the entry of four paws into an arm. Open-arm entry time (time spent in open arms) was expressed as a percentage of the total entry time (% of time), and the number of open-arm entries was expressed as a percentage of the number of total entries (% of visits). I.c.v. administration was performed as described previously [21–24]. Briefly, a 28-gauge stainless steel needle attached to a 0.05 ml Hamilton syringe was inserted perpendicularly through the skull into the brain. The site of injection was 2 mm from either side of the midline on a line drawn through the anterior base of the ears. C5a was dissolved in artificial cerebrospinal fluid (ACSF: 138.9 mM NaCl, 3.4 mM KCl, 1.3 mM CaCl2 , 4.0 mM NaHCO3 , 0.6 mM NaH2 PO4 , and 5.6 mM glucose, at pH 7.4). The dosages of C5a (0.03–0.3 pmol/mouse) were determined by preliminary experiment. C5a in 4 l ACSF was i.c.v. administered 20 min before the test. An antagonist of the DP1 receptor was i.c.v. co-administered with C5a 20 min before the test. Other antagonists were i.p. administered 30 min before the test. Under our experimental conditions, all antagonists and inhibitor did not change any parameters in the elevated-plus maze test, as previously described [7,13]. The total number of visits to open and closed arms, and the cumulative time spent in open and closed arms were measured on a monitor through a video camera system. The data were checked by observers unaware of the experimental groups. The EPM test was started at 11:00 a.m. during the light phase of the light/dark cycle. 2.4. Statistical analysis Values are expressed as the means ± SEM. Statistical comparisons between groups were performed using one-way analysis of
Fig. 1. Anxiolytic-like activity of C5a after central administration in the elevated plus-maze (EPM) test in mice. C5a at a dose of 0.03–0.3 pmol/mouse was i.c.v. administered 20 min before the test. The percentages of time spent in (A) and visits to (B) open arms, and total visits (C) to both open and closed arms during the test were measured for 5 min. Each value is expressed as the mean ± SEM (n = 5–9). *P < 0.05, **P < 0.01, compared with the ACSF-treated control group.
variance (ANOVA) followed by Fisher’s test. P values less than 0.05 were considered significant. 3. Results 3.1. C5a exhibits anxiolytic-like activity in the elevated plus-maze test We investigated whether C5a exhibits anxiolytic-like activity after central administration in the elevated plus-maze test in mice. I.c.v. administered C5a at a dose of 0.3 pmol/mouse significantly increased the percentages of the time and visits to the open arms for 5 min (Fig. 1A and B). C5a did not change the total visits to open and closed arms (Fig. 1C), suggesting that C5a had no effect on locomotor activity. Thus, we found that centrally administered C5a has anxiolytic-like activity in mice. C5a-desArg, C-terminal Arg residue-truncated C5a lucking affinity for C5a receptor, did not exhibit anxiolytic-like activity at a dose of 0.3 nmol/mouse after central administration (Fig. 2), suggesting that C5a exhibits anxiolytic-like activity in a manner dependent on C5a receptor. 3.2. Anxiolytic-like activity of C5a is mediated by activation of the PGD2 –DP1 receptor system We have reported that centrally administrated C5a stimulates food intake via activation of the PGD2 −DP1 receptor system [16], suggesting that PGD2 is one of the mediators of C5a. To investigate whether the anxiolytic effect of C5a is mediated via the PGD2 −DP1 receptor system, we used a cyclooxygenase (COX) inhibitor, indomethacin, and a DP1 receptor-antagonist, BWA868C. C5a
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Fig. 2. Effect of C5a-desArg on the anxiety-related behavior after central administration in mice. C5a-desArg and C5a at a does of 0.3 pmol/mouse was i.c.v. administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 5). *P < 0.05, **P < 0.01, compared with the ACSF-treated control group.
(0.3 pmol/mouse, i.c.v.)-induced increases in percentages of time and visits to open arms were completely blocked by indomethacin (10 mg/kg, i.p.), as shown in Fig. 3A and B. Indomethacin alone did not have any effect on anxiety-related behavior (Fig. 3). The
Fig. 4. Effect of DP1 receptor antagonist on the anxiolytic-like activity of C5a. C5a (0.3 pmol/mouse, i.c.v.) was co-administered BWA868 C (1.6 nmol/mouse), an antagonist selective for DP1 receptor, 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
anxiolytic-like activity of C5a was significantly blocked by coadministration with BWA868C (1.6 nmol/mouse, i.c.v.), as shown in Fig. 4A and B. BWA868C alone did not have any effect on anxiety-related behavior (Fig. 4). Thus, we demonstrated that the anxiolytic-like activity of C5a after central administration is evidently mediated by activation of the PGD2 –DP1 receptor system.
3.3. Anxiolytic-like activity of C5a is associated with activation of the adenosine A2A and GABAA receptors, downstream of the PGD2 –DP1 receptor system
Fig. 3. Effect of COX inhibitor on the anxiolytic-like activity of C5a. Indomethacin (10 mg/kg), an inhibitor of COX, was i.p. pretreated 30 min before the EPM test, and C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001 compared with each group.
We investigated the mechanism for anxiolytic-like activity by C5a, downstream of the PGD2 –DP1 receptor system. Thus, we tested the effect of A2A and GABAA receptor antagonists on the anxiolytic-like activity of C5a. Pretreatment with SCH58261, an A2A receptor antagonist (0.1 mg/kg, i.p.), significantly blocked increases in percentages of time and visits to the open arms after administration of C5a (0.3 pmol/mouse, i.c.v.), as shown in Fig. 5A and B. SCH58261 itself did not have any effect on anxiety-related behavior (Fig. 5). C5a-induced anxiolytic-like activity was also blocked by pretreatment with a specific antagonist for the GABA binding site, bicuculline (5 mg/kg, i.p., Fig. 6), but not by an antagonist for the benzodiazepine binding site, flumazenil (data not shown). The anxiolytic-like activity of C5a was not blocked by WAY100135 or SCH23390, an antagonist of 5HT1A or D1 receptors, respectively (Fig. 7). This is consistent with our previous report that PGD2 -induced anxiolytic activity was blocked by bicuculine but not flumazenil, WAY100135, and SCH23390 [7]. Taken together, the anxiolytic-like activity of C5a may be also mediated by adenosine A2A and GABAA receptors.
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Fig. 5. Effect of adenosine A2A antagonist on the anxiolytic-like activity of C5a. SCH58261 (0.1 mg/kg), an antagonist of adenosine A2A receptor, was i.p. pretreated 30 min before the EPM test. C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 8–10). *P < 0.05, **P < 0.01, compared with each group.
Fig. 6. Effects of GABAA receptor antagonists on the anxiolytic-like activity of C5a. Bicuculline (5 mg/kg), an antagonist for the GABA-binding site of GABAA receptor, was i.p. pretreated 30 min before the EPM test, and C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
4. Discussion We found for the first time that centrally administered C5a exhibits anxiolytic-like activity in the EPM test in mice. This is the novel central action of C5a on emotional behavior. It has been reported that C5a receptor is present in most areas of the normal human CNS [15]. Another receptor for C5a, the C5a-like receptor (C5L2) is also expressed on cells in the CNS, and binds to C5a and its degradation product C5a-desArg; however, C5a-desArg was inactive in the anxiolytic activity. These results suggest that C5a-induced anxiolytic-like activity is dependent on C5a receptor rather than C5L2 receptor. It has been reported that the central complement system might be activated during acute brain injury, such as ischemia and trauma, and chronic neurodegeneration, including Alzheimer’s disease and Huntington’s disease [25–27]. Furthermore, C5a receptor is expressed concomitant with the onset of clinical disease on infiltrating inflammatory cells and on resident microglia, astrocytes and neurones in the Lewis rat model of experimental autoimmune encephalomyelitis (EAE) [28]. Further investigations will elucidate the biological significance of anxiolytic activity by C5a in physiological and pathological conditions. A number of cytokines are thought be released during activation of the immune system. Indeed, cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-␣ increase anxiety-like behavior in the EPM test [29,30]. Corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN), which is activated by IL-1 [31], also shows anxiety behavior after central administration [32], suggesting that many endogenous substances secreted during CNS disease might increase anxiety-like behavior. In contrast, we found that C5a decreased anxiety. We have also demonstrated that another anaphylatoxin, complement C3a exhibited an anxiolytic effect after
central administration through activation of the PGE2 –EP4 receptor system (unpublished observation). Thus, we hypothesize that the central complement system might suppress excessive anxiety-like behavior during CNS disease. In the current study, we found that C5a shows anxiolyticlike activity through the PGD2 –DP1 receptor system. It was reported that centrally administered C5a increased hypothalamic expression of mRNA encoding COX-2 but not COX-1. COX-2 was co-localized with L-PGDS in the leptomeninges and choroid plexus [8], and L-PGDS and DP1 was observed in parenchyma cells of the hypothalamus [6]. We previously reported that PGD2 exhibits anxiolytic-like activity via activation of adenosine A2A and GABAA receptors [7]. It has been hypothesized that central PGD2 induces sleep via A2A and GABAA receptors [5,33], which was consistent with anxiolytic pathway activated in response to C5a as well as PGD2 after central administration [7]. The GABAA receptor is a pentameric heterooligometric protein with binding sites for GABA, benzodiazepines (BZD), barbiturates, steroids, etc. C5a-inducecd anxiolytic-like activity was blocked by pretreatment with a specific antagonist for the GABA binding site, but not by an antagonist for the BZD binding site. These results suggest that C5a shows an anxiolytic-like effect after activating the GABA binding site, probably by stimulating presynaptic GABA release, but not after activating the BZD binding site. Thus, the mechanism underlying anxiolytic-like activity of C5a was quite different from that of BZD, general anxiolytic drugs. We have found that central PGE2 exhibits anxiolytic-like activity coupled to serotonin 5-HT1A and dopamine D1 receptors, downstream of the EP1 /EP4 receptors [13]; however, the anxiolytic-like activity of C5a was not blocked by 5-HT1A and D1 receptor antagonists, suggesting that C5a-induced anxiolytic-like
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Furthermore, C5a-induced anxiolytic-like activity was mediated via adenosine A2A and GABAA receptors downstream of DP1 receptor.
Acknowledgment This work was supported in part by grants-in-aid from the Japan Science and Technology Agency (CREST) to KO, MY and KW.
References
Fig. 7. Effects of antagonists of serotonin 5-HT1A or dopamine D1 receptor on the anxiolytic-like activity of C5a. WAY100135 (10 mg/kg) or SCH23390 (30 g/kg), antagonists of 5-HT1A and D1 receptor, respectively, was i.p. pretreated 30 min before the EPM test. C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
activity might be independent of the activation of these receptors. It is reported that dopamine D2 receptor forms functional heteromeric complexes with adenosine A2A receptor in the CNS [34]. Their polymorphisms have been revealed to contribute to responses to caffeine-induced anxiety [35]. The activation of A2A receptors induces sleep, whereas the D2 receptor is important for the maintenance of wakefulness [36]. Opposing effects of A2A and D2 receptors have also been shown at the levels of neurotransmitter release, receptor binding, and gene expression [36,37]. Further investigations will elucidate the interaction of A2A and D2 receptors in emotional regulation, downstream of the C5a and PGD2 systems. C5a stimulates food intake through activation of the PGD2 –DP1 receptor system coupled to neuropeptide Y (NPY)–Y1 receptor [16]; however, the PGD2 -induced anxiolytic-like activity is coupled to A2A and GABAA but not Y1 receptors [7], These results suggest that neural pathways regulating emotional behavior and food intake may not be completely common. Natural food proteins-derived bioactive peptides after enzymatic digestion have been identified. These peptides sometime act as agonists for complement receptors, including C5a receptor, or release PGs. We have reported that anxiolytic-like activity induced by a tripeptide rubimetide is mediated by the PGD2 system [38]. Further investigations will reveal whether the anxiolytic activity of the peptides derived from food proteins activating the PGD2 –DP1 receptor system potentially affects emotional responses in the postprandial state. In conclusion, we found that centrally administered complement C5a exhibited anxiolytic-like activity in the elevated plus-maze test in mice. We also demonstrated that the anxiolyticlike activity of C5a was mediated by the PGD2 –DP1 system.
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Contents lists available at SciVerse ScienceDirect
Prostaglandins and Other Lipid Mediators
Complement C5a exhibits anxiolytic-like activity via the prostaglandin D2 −DP1 receptor system coupled to adenosine A2A and GABAA receptors Chihiro Miyamoto a,b , Mariko Yoshida a,b , Masaaki Yoshikawa a,b , Takafumi Mizushige a,c , Kousaku Ohinata a,b,∗ a
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 322-0012, Japan c Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto 606-8501, Japan b
a r t i c l e
i n f o
Article history: Received 25 January 2012 Received in revised form 27 March 2012 Accepted 30 March 2012 Available online 6 April 2012 Keywords: Anxiolytic activity Complement C5a Prostaglandin D2 DP1 receptor Adenosine A2A receptor GABAA receptor
a b s t r a c t We have recently found that central PGD2 exhibits anxiolytic-like activity. Here we show that complement C5a exhibits anxiolytic-like activity via the PGD2 system. Centrally administered C5a had anxiolytic-like activity at a dose of 0.3 pmol/mouse in the elevated plus-maze test in mice. C5a-induced anxiolytic-like activity was inhibited by indomethacin, a cyclooxygenase inhibitor, or BWA868C, an antagonist of DP1 receptor for PGD2 , respectively. The anxiolytic effect of C5a was also blocked by SCH58261 or bicuculline, antagonists of adenosine A2A and GABAA receptors, respectively, which were activated downstream of PGD2 –DP1 receptor. These results suggest that C5a exhibits anxiolytic-like activity via the PGD2 –DP1 receptor system coupled to the activation of adenosine A2A and GABAA receptors.
1. Introduction Prostaglandin (PG) D2 is the most abundant PG produced in the central nervous system (CNS) [1] and is involved in various central actions, including sleep induction, anxiolytic-like activity, hypothermia and attenuation of the pain response [2–7]. PGD2 is produced endogenously from arachidonic acid, via PGH2 , by lipocalin-type PGD synthase (L-PGDS), which is located in the arachnoid membrane and choroid plexus of the brain [8,9]. DP1 receptor selective for PGD2 has been isolated and characterized as a seven-transmembrane Gs protein-coupled rhodopsin-type receptor [10] In situ hybridization and immunohistochemistry assays with mice have revealed that the DP1 receptor is present in the arachnoid membrane in the basal forebrain [11,12]. We have recently reported that centrally administrated PGD2 stimulates food intake and exhibits anxiolytic-like activity via the DP1 receptor, and both L-PGDS- and DP1 -like immunoreactivity was detected in the hypothalamus, an important site for regulation of food intake
∗ Corresponding author at: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan. Tel.: +81 774 38 3733, fax: +81 774 38 3774. E-mail address: [email protected] (K. Ohinata). 1098-8823/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prostaglandins.2012.03.004
© 2012 Elsevier Inc. All rights reserved.
and emotional behavior [6,7]. The anxiolytic-like activity of PGD2 was mediated via activating the adenosine A2A and GABAA receptors. In addition, we have found that PGE2 , a structure isomer of PGD2 , exhibits anxiolytic-like activity in a manner dependent on the serotonin 5-HT1A , dopamine D1 and GABAA receptors, downstream of the EP1 /EP4 receptors [13]. The complement system, a series of proteins activated in response to pathogen invasion, plays an important role in the peripheral immune system [14]. Complement C5a is a 74-amino acid polypeptide derived from C5 by enzymatic degradation during activation of the complement system [14]. C5a has a variety of physiological activities, such as stimulation of histamine secretion in mast cells, increased capillary vessel permeability, contraction of smooth muscle, chemotaxic activity, and facilitation of phagocyte mobilization [14]. C5a is also called anaphylatoxin, since it induces anaphylactic-like reaction after peripheral administration. It has been revealed that the complement system, including C5a and its receptor, is present in the CNS as well as the peripheral immune system [15]. We have also found that C5a stimulates food intake after central administration via the PGD2 system [16], which is associated with emotional behavior [7]. Thus, we investigated whether centrally administrated C5a exhibits anxiolytic activity, and the mechanism underlying its activity.
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2. Materials and methods 2.1. Materials Human complement C5a was purchased from Sigma Chemical Co. (St. Louis, MO); and DP1 receptor-antagonist BWA868C was from Cayman Chemical (Ann Arbor, MI). SCH58261, an adenosine A2A receptor antagonist; and bicuculline, a ␥-aminobutyric acid type A (GABAA ) antagonist; were obtained from Tocris Bioscience (Bristol, UK). C5a-desArg was purchased from Calbiochem (Darmstadt, Germany) 2.2. Animals Four-week-old male ddY mice, 20–24 g body weight, for intracerebroventricular (i.c.v.) administration, respectively, were obtained from SLC (Shizuoka, Japan). This ddY strain, a closed colony with a rapid growth rate and high reproductive potential, has frequently been used in various biomedical researches, including behavioral pharmacological tests, as previously described [17–21]. All animals were housed in a temperature-controlled room (23 ◦ C) on a 12 hr light–dark cycle with lights on at 07:00. All animals had free access to food pellets and water. All experiments were approved by Kyoto University Ethics Committee for Animal Research Use. All animals were euthanized by an overdose of anesthesia drugs after the experiment. 2.3. Elevated plus-maze test Anxiolytic-like behavior was measured using the elevated plusmaze (EPM) test, which was performed as described previously [17–20]. Four arms (25 cm long × 5 cm wide) were placed 50 cm above the ground. Two opposite arms were delimited by acrylic vertical walls (15 cm high, closed arms), whereas the other two, opposite arms had unprotected edges (open arms). A mouse was placed in the center of the maze facing an open arm and observed for 5 min to measure the cumulative time and frequency of entries into open and closed arms. Arm entry was defined as the entry of four paws into an arm. Open-arm entry time (time spent in open arms) was expressed as a percentage of the total entry time (% of time), and the number of open-arm entries was expressed as a percentage of the number of total entries (% of visits). I.c.v. administration was performed as described previously [21–24]. Briefly, a 28-gauge stainless steel needle attached to a 0.05 ml Hamilton syringe was inserted perpendicularly through the skull into the brain. The site of injection was 2 mm from either side of the midline on a line drawn through the anterior base of the ears. C5a was dissolved in artificial cerebrospinal fluid (ACSF: 138.9 mM NaCl, 3.4 mM KCl, 1.3 mM CaCl2 , 4.0 mM NaHCO3 , 0.6 mM NaH2 PO4 , and 5.6 mM glucose, at pH 7.4). The dosages of C5a (0.03–0.3 pmol/mouse) were determined by preliminary experiment. C5a in 4 l ACSF was i.c.v. administered 20 min before the test. An antagonist of the DP1 receptor was i.c.v. co-administered with C5a 20 min before the test. Other antagonists were i.p. administered 30 min before the test. Under our experimental conditions, all antagonists and inhibitor did not change any parameters in the elevated-plus maze test, as previously described [7,13]. The total number of visits to open and closed arms, and the cumulative time spent in open and closed arms were measured on a monitor through a video camera system. The data were checked by observers unaware of the experimental groups. The EPM test was started at 11:00 a.m. during the light phase of the light/dark cycle. 2.4. Statistical analysis Values are expressed as the means ± SEM. Statistical comparisons between groups were performed using one-way analysis of
Fig. 1. Anxiolytic-like activity of C5a after central administration in the elevated plus-maze (EPM) test in mice. C5a at a dose of 0.03–0.3 pmol/mouse was i.c.v. administered 20 min before the test. The percentages of time spent in (A) and visits to (B) open arms, and total visits (C) to both open and closed arms during the test were measured for 5 min. Each value is expressed as the mean ± SEM (n = 5–9). *P < 0.05, **P < 0.01, compared with the ACSF-treated control group.
variance (ANOVA) followed by Fisher’s test. P values less than 0.05 were considered significant. 3. Results 3.1. C5a exhibits anxiolytic-like activity in the elevated plus-maze test We investigated whether C5a exhibits anxiolytic-like activity after central administration in the elevated plus-maze test in mice. I.c.v. administered C5a at a dose of 0.3 pmol/mouse significantly increased the percentages of the time and visits to the open arms for 5 min (Fig. 1A and B). C5a did not change the total visits to open and closed arms (Fig. 1C), suggesting that C5a had no effect on locomotor activity. Thus, we found that centrally administered C5a has anxiolytic-like activity in mice. C5a-desArg, C-terminal Arg residue-truncated C5a lucking affinity for C5a receptor, did not exhibit anxiolytic-like activity at a dose of 0.3 nmol/mouse after central administration (Fig. 2), suggesting that C5a exhibits anxiolytic-like activity in a manner dependent on C5a receptor. 3.2. Anxiolytic-like activity of C5a is mediated by activation of the PGD2 –DP1 receptor system We have reported that centrally administrated C5a stimulates food intake via activation of the PGD2 −DP1 receptor system [16], suggesting that PGD2 is one of the mediators of C5a. To investigate whether the anxiolytic effect of C5a is mediated via the PGD2 −DP1 receptor system, we used a cyclooxygenase (COX) inhibitor, indomethacin, and a DP1 receptor-antagonist, BWA868C. C5a
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Fig. 2. Effect of C5a-desArg on the anxiety-related behavior after central administration in mice. C5a-desArg and C5a at a does of 0.3 pmol/mouse was i.c.v. administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 5). *P < 0.05, **P < 0.01, compared with the ACSF-treated control group.
(0.3 pmol/mouse, i.c.v.)-induced increases in percentages of time and visits to open arms were completely blocked by indomethacin (10 mg/kg, i.p.), as shown in Fig. 3A and B. Indomethacin alone did not have any effect on anxiety-related behavior (Fig. 3). The
Fig. 4. Effect of DP1 receptor antagonist on the anxiolytic-like activity of C5a. C5a (0.3 pmol/mouse, i.c.v.) was co-administered BWA868 C (1.6 nmol/mouse), an antagonist selective for DP1 receptor, 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
anxiolytic-like activity of C5a was significantly blocked by coadministration with BWA868C (1.6 nmol/mouse, i.c.v.), as shown in Fig. 4A and B. BWA868C alone did not have any effect on anxiety-related behavior (Fig. 4). Thus, we demonstrated that the anxiolytic-like activity of C5a after central administration is evidently mediated by activation of the PGD2 –DP1 receptor system.
3.3. Anxiolytic-like activity of C5a is associated with activation of the adenosine A2A and GABAA receptors, downstream of the PGD2 –DP1 receptor system
Fig. 3. Effect of COX inhibitor on the anxiolytic-like activity of C5a. Indomethacin (10 mg/kg), an inhibitor of COX, was i.p. pretreated 30 min before the EPM test, and C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, ***P < 0.001 compared with each group.
We investigated the mechanism for anxiolytic-like activity by C5a, downstream of the PGD2 –DP1 receptor system. Thus, we tested the effect of A2A and GABAA receptor antagonists on the anxiolytic-like activity of C5a. Pretreatment with SCH58261, an A2A receptor antagonist (0.1 mg/kg, i.p.), significantly blocked increases in percentages of time and visits to the open arms after administration of C5a (0.3 pmol/mouse, i.c.v.), as shown in Fig. 5A and B. SCH58261 itself did not have any effect on anxiety-related behavior (Fig. 5). C5a-induced anxiolytic-like activity was also blocked by pretreatment with a specific antagonist for the GABA binding site, bicuculline (5 mg/kg, i.p., Fig. 6), but not by an antagonist for the benzodiazepine binding site, flumazenil (data not shown). The anxiolytic-like activity of C5a was not blocked by WAY100135 or SCH23390, an antagonist of 5HT1A or D1 receptors, respectively (Fig. 7). This is consistent with our previous report that PGD2 -induced anxiolytic activity was blocked by bicuculine but not flumazenil, WAY100135, and SCH23390 [7]. Taken together, the anxiolytic-like activity of C5a may be also mediated by adenosine A2A and GABAA receptors.
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Fig. 5. Effect of adenosine A2A antagonist on the anxiolytic-like activity of C5a. SCH58261 (0.1 mg/kg), an antagonist of adenosine A2A receptor, was i.p. pretreated 30 min before the EPM test. C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 8–10). *P < 0.05, **P < 0.01, compared with each group.
Fig. 6. Effects of GABAA receptor antagonists on the anxiolytic-like activity of C5a. Bicuculline (5 mg/kg), an antagonist for the GABA-binding site of GABAA receptor, was i.p. pretreated 30 min before the EPM test, and C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
4. Discussion We found for the first time that centrally administered C5a exhibits anxiolytic-like activity in the EPM test in mice. This is the novel central action of C5a on emotional behavior. It has been reported that C5a receptor is present in most areas of the normal human CNS [15]. Another receptor for C5a, the C5a-like receptor (C5L2) is also expressed on cells in the CNS, and binds to C5a and its degradation product C5a-desArg; however, C5a-desArg was inactive in the anxiolytic activity. These results suggest that C5a-induced anxiolytic-like activity is dependent on C5a receptor rather than C5L2 receptor. It has been reported that the central complement system might be activated during acute brain injury, such as ischemia and trauma, and chronic neurodegeneration, including Alzheimer’s disease and Huntington’s disease [25–27]. Furthermore, C5a receptor is expressed concomitant with the onset of clinical disease on infiltrating inflammatory cells and on resident microglia, astrocytes and neurones in the Lewis rat model of experimental autoimmune encephalomyelitis (EAE) [28]. Further investigations will elucidate the biological significance of anxiolytic activity by C5a in physiological and pathological conditions. A number of cytokines are thought be released during activation of the immune system. Indeed, cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-␣ increase anxiety-like behavior in the EPM test [29,30]. Corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN), which is activated by IL-1 [31], also shows anxiety behavior after central administration [32], suggesting that many endogenous substances secreted during CNS disease might increase anxiety-like behavior. In contrast, we found that C5a decreased anxiety. We have also demonstrated that another anaphylatoxin, complement C3a exhibited an anxiolytic effect after
central administration through activation of the PGE2 –EP4 receptor system (unpublished observation). Thus, we hypothesize that the central complement system might suppress excessive anxiety-like behavior during CNS disease. In the current study, we found that C5a shows anxiolyticlike activity through the PGD2 –DP1 receptor system. It was reported that centrally administered C5a increased hypothalamic expression of mRNA encoding COX-2 but not COX-1. COX-2 was co-localized with L-PGDS in the leptomeninges and choroid plexus [8], and L-PGDS and DP1 was observed in parenchyma cells of the hypothalamus [6]. We previously reported that PGD2 exhibits anxiolytic-like activity via activation of adenosine A2A and GABAA receptors [7]. It has been hypothesized that central PGD2 induces sleep via A2A and GABAA receptors [5,33], which was consistent with anxiolytic pathway activated in response to C5a as well as PGD2 after central administration [7]. The GABAA receptor is a pentameric heterooligometric protein with binding sites for GABA, benzodiazepines (BZD), barbiturates, steroids, etc. C5a-inducecd anxiolytic-like activity was blocked by pretreatment with a specific antagonist for the GABA binding site, but not by an antagonist for the BZD binding site. These results suggest that C5a shows an anxiolytic-like effect after activating the GABA binding site, probably by stimulating presynaptic GABA release, but not after activating the BZD binding site. Thus, the mechanism underlying anxiolytic-like activity of C5a was quite different from that of BZD, general anxiolytic drugs. We have found that central PGE2 exhibits anxiolytic-like activity coupled to serotonin 5-HT1A and dopamine D1 receptors, downstream of the EP1 /EP4 receptors [13]; however, the anxiolytic-like activity of C5a was not blocked by 5-HT1A and D1 receptor antagonists, suggesting that C5a-induced anxiolytic-like
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Furthermore, C5a-induced anxiolytic-like activity was mediated via adenosine A2A and GABAA receptors downstream of DP1 receptor.
Acknowledgment This work was supported in part by grants-in-aid from the Japan Science and Technology Agency (CREST) to KO, MY and KW.
References
Fig. 7. Effects of antagonists of serotonin 5-HT1A or dopamine D1 receptor on the anxiolytic-like activity of C5a. WAY100135 (10 mg/kg) or SCH23390 (30 g/kg), antagonists of 5-HT1A and D1 receptor, respectively, was i.p. pretreated 30 min before the EPM test. C5a (0.3 pmol/mouse, i.c.v.) was administered 20 min before the test. Each value is expressed as the mean ± SEM (n = 4). *P < 0.05, **P < 0.01, compared with each group.
activity might be independent of the activation of these receptors. It is reported that dopamine D2 receptor forms functional heteromeric complexes with adenosine A2A receptor in the CNS [34]. Their polymorphisms have been revealed to contribute to responses to caffeine-induced anxiety [35]. The activation of A2A receptors induces sleep, whereas the D2 receptor is important for the maintenance of wakefulness [36]. Opposing effects of A2A and D2 receptors have also been shown at the levels of neurotransmitter release, receptor binding, and gene expression [36,37]. Further investigations will elucidate the interaction of A2A and D2 receptors in emotional regulation, downstream of the C5a and PGD2 systems. C5a stimulates food intake through activation of the PGD2 –DP1 receptor system coupled to neuropeptide Y (NPY)–Y1 receptor [16]; however, the PGD2 -induced anxiolytic-like activity is coupled to A2A and GABAA but not Y1 receptors [7], These results suggest that neural pathways regulating emotional behavior and food intake may not be completely common. Natural food proteins-derived bioactive peptides after enzymatic digestion have been identified. These peptides sometime act as agonists for complement receptors, including C5a receptor, or release PGs. We have reported that anxiolytic-like activity induced by a tripeptide rubimetide is mediated by the PGD2 system [38]. Further investigations will reveal whether the anxiolytic activity of the peptides derived from food proteins activating the PGD2 –DP1 receptor system potentially affects emotional responses in the postprandial state. In conclusion, we found that centrally administered complement C5a exhibited anxiolytic-like activity in the elevated plus-maze test in mice. We also demonstrated that the anxiolyticlike activity of C5a was mediated by the PGD2 –DP1 system.
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