Agmatine attenuates lipopolysaccharide induced anorexia and sickness behavior in rats

doi:10.1016/j.pbb.2015.02.013

Pharmacology Biochemistry and Behavior

Volume 132, May 2015, Pages 108-114

https://doi.org/10.1016/j.pbb.2015.02.013 Get rights and content

Highlights

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LPS exhibited hyperthermia, hypophagia, reduced water intake, anxiety and depression in rats.
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LPS treatment elevated interleukin-6 and TNF-α level in rat serum samples.
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Agmatine attenuated LPS induced hyperthermia, anorexia, depression and anxiety.
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Agmatine pretreatment suppressed LPS induced elevation in interleukin-6 and TNF-α levels.

Abstract

Sickness behavior is characterized by lethargy, reduced appetite, anhedonia and anxiety. It can be induced in experimental animals by bacterial endotoxin, lipopolysaccharide (LPS). We investigated the impact of intracerebroventricular agmatine injections (5–20 μg/rat, icv) on sickness behavior induced by LPS (100 μg/rat, ip) in rats. Rats challenged with LPS demonstrated hyperthermia, anorexia, anxiety, depression like phenomenon and reduction in body weights. Additionally, mediators of sickness behaviors, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) level in LPS treated rat serum were also increased. The present study revealed that these LPS induced symptoms of sickness behavior including anorexia were normalized by pretreatment with agmatine. The IL-6 and TNF-α serum levels were also normalized in agmatine pretreated rats. It is anticipated that agmatine may suppress LPS induced sickness behavior by inhibiting proinflammatory pathway and/or activity circuitry in brain. This study suggests that agmatine may be an important therapeutic target in the treatment of anorexia and other neurological abnormalities associated with bacterial infection.

Introduction

Agmatine, an endogenous amine is synthesized through decarboxylation of L-arginine by arginine decarboxylase (ADC) and widely distributed throughout the body including brain. It is a neurotransmitter and/or neuromodulator (Raasch et al., 1995, Reis and Regunathan, 2000) and exhibits several biological effects by interacting with certain receptors and neuronal pathways in CNS. Agmatine activates α₂-adrenoceptors and imidazoline receptors (Reis and Regunathan, 2000, Halaris and Plietz, 2007), and blocks N-methyl D-aspartate (NMDA) receptors (Yang and Reis, 1999), nicotinic receptors and 5-HT3 receptors. Additionally, it competitively inhibits nitric oxide (NO) synthase (Auguet et al., 1995). In experimental studies, agmatine showed a variety of pharmacological effects including anticonvulsant, anxiolytic, antinociceptive, antidepressant, antistress and neuroprotective effects (Reis and Regunathan, 2000, Halaris and Plietz, 2007, Gilad and Gilad, 2000, Gilad et al., 2005, Olmos et al., 1999, Wang et al., 2006, Zhu et al., 2003, Zhu et al., 2008, Taksande et al., 2010 Taksande et al., 2013). In addition, it augments the release of insulin from pancreatic β-cells (Sener et al., 1989), leutinizing hormone-releasing hormone (LHRH) from the hypothalamus (Kalra et al., 1995) and gastrin secretion. Several reports indicated that agmatine may be a useful substance in the treatment of number of CNS disorders ranging from pain to substance abuse and dependence. Few studies have demonstrated its orexigenic activity (Taksande et al., 2011, Prasad and Prasad, 1996) and suggest that agmatine may be an additional regulator of feeding behavior (Taksande et al., 2011, Prasad and Prasad, 1996). However, the role of agmatine in infection associated anorexia and sickness behavior remains poorly investigated.

Sickness behavior is a behavioral complex induced typically by infections, inflammation, tissue injury or immune trauma and mediated by proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α. Its characteristic features include anxiety, anorexia, depressed activity, hyperthermia, loss of interest in usual activities and sleepiness etc. (Becskei et al., 2008). In experimental animals, sickness behavioral response can be induced by administration of gram negative bacterial component, lipopolysaccharide (LPS) released during sepsis or severe infection. Importantly, Sastre et al. (1998) reported that LPS reduces endogenous agmatine levels by stimulating its degrading enzyme, agmatinase and/or inhibiting stimulatory enzyme ADC. The results of recent studies that agmatine suppresses LPS induced hyperthermia, hepatic failure (Aricioglu and Regunathan, 2005, El-Agamy et al., 2014) and NO synthesis in cultured microglia (Abe et al., 2000) indicated its role in sickness behavior. Considering the presence of agmatine in brain system known to be involved in food consumption, inflammation, pain, anxiety and depressive behavior (Taksande et al., 2009, Taksande et al., 2010; Fairbanks et al., 2000) we hypothesized that agmatine would prevent responses to infection such as sickness behavior. This study investigated the effect of agmatine on various indicators of sickness behavior including anorexia, hyperthermia, anxiety, depression, and body weight changes following intraperitoneal (ip) injections of LPS in rats. We also quantified the levels of TNF and IL-6 in serum samples to elucidate the central mechanism behind the attenuation of sickness behavior by agmatine.

Section snippets

Subjects

Adult Sprague–Dawley rats (225–250 g) of either sex were procured from the National Institute of Nutrition, Hyderabad, India and group (n = 5) housed in acrylic cages (24 × 17 × 12 cm) at an ambient temperature (25 ± 2 °C), relative humidity (50 ± 5%), with a 12:12 h light–dark cycle (lights on at 0600 h). Animals had free access to standard pellet chow (Trimurti Feeds, Nagpur, India; provide 3.30 kcal/g with 23.4% protein, 4.5% fat and 72.1% carbohydrate, which is primarily in the form of complex

Agmatine attenuates LPS effect on food intake, body weight and water intake

As shown in Fig. 1, LPS injection (100 μg/kg, ip) significantly reduced food consumption at 4, 6, 12, and 24 h time points as compared to saline treated controls. At these time points, the rats treated with LPS consumed respectively 1.75 ± 0.69 g, 3.73 ± 0.98 g, 8.78 ± 2.03 g and 18.75 ± 2.16 g as compared to 5.84 ± 1.54 g, 9.38 ± 1.49 g, 14 ± 3.12 g and 24.24 ± 4.36 g at 4, 6, 12 and 24 h in the corresponding saline control. The food intake was reduced by 70% at 4 h (P < 0.05), 60% at 6 h (P < 0.001) and by 23% at 12 h (P <

Discussion

Consistent with previous reports (Becskei et al., 2008, Hollis et al., 2011), we found that rats challenged with LPS showed significant anorexia, body weight loss, hyperthermia, anxiety as well as depressive like behavior. Additionally LPS induced an increase in serum cytokine levels (IL-6 and TNF-α). The present reports are the first to demonstrate that pretreatment with agmatine attenuated these components of sickness behavior caused by LPS.

Sickness behavior is a functional homeostatic

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Citation Excerpt :
Similarly, no reports of adverse events so far has been reported since the introduction of agmatine sulfate to commerce for body builders, based on unsubstantiated claims, in 2007 at recommended dosage up to 1.0 g/day and later, starting in 2012, at up to 2.0 g/day. However, the role of agmatine in altering feeding behavior in several pathological conditions like bacterial infections, stress, anorexia nervosa, obesity, cachexia and alcohol misuse, have also been demonstrated (Taksande et al., 2011, 2015a, 2015b, 2017; Benítez et al., 2018). The orexogenic behavior observed was not associated with weight gain and so differential physiological role of agmatine as mediator/regulator of feeding behavior and satiety is foreseen (Table 4).
Agmatine, an endogenous polyamine in CNS, is derived from arginine by dearboxylation. Like polyamines, agmatine has been studied for its neuroprotetive effects. At present, a large body of experimental evidences has been gathered that demonstrate the neuroprotective effects of agmatine. The neuroprotective effects have been observed in various CNS cell lines and animal models against the excitotocity, oxidative damage, corticosteroidid induced neurotoxicity, ischemic/hypoxic or oxygen-glucose deprivation toxicity, spinal cord injury and traumatic brain injury. The studies have been extended to rescue of retinal ganglion cells from toxicities. The mechanistic studies suggest that neuroprotection offered by agmatine can be assigned to its multimolecular biological effects. These include its action as glutamatergic receptor antagonist, α₂-adrenoceptor agonist, imidazoline binding site ligand, NOS inhibitor, ADP ribosylation inhibitor, and blocker of ATP-sensitive potassium and voltage-gated calcium channels, anti-apoptotic and antioxidant. Its action as regulator for polyamine synthesis, insulin release assists the neuroprotection.
The cumulative evidences of preclinical studies support the possible use of agmatine as an agent for neuronal damage and neurodegenerative diseases. However, it will be hasty to assert and promote agmatine as a novel therapeutic agent for neuroprotection. The review is focused on the role of agmatine in different types and mechanisms of neural injuries. The aspects of concern like dose range, pharmacokinetics of exogenous agmatine, levels of endogenous agmatine during events of injury etc. has to be addressed.

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Agmatine attenuates lipopolysaccharide induced anorexia and sickness behavior in rats

Highlights

Abstract

Introduction

Section snippets

Subjects

Agmatine attenuates LPS effect on food intake, body weight and water intake

Discussion

Brain Res

Physiol Behav

Jpn J Pharmacol

Brain Behav Immun

Immunol Allergy Clin North Am

Behav Brain Res

Pharmacol Biochem Behav

Neurosci Lett

J Neuroimmunol

Life Sci

Neurosci Lett

J Nutr

Neuropharmacology

Neuropharmacology

Brain Res

Behav Brain Res

Physiol Behav

J Neuroimmunol

Physiol Behav

Life Sci

Trends Pharmacol Sci

Brain Res

Biochem Pharmacol

Brain Behav Immun