Chronic agmatine treatment prevents olanzapine-induced obesity and metabolic dysregulation in female rats.

Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with high obesogenic potential. However, the exact mechanism by which it causes its metabolic dysregulation remains poorly understood. In this study, we investigated the effect of agmatine in olanzapine-induced metabolic derangements in Female Sprague-Dawley rats. Repeated olanzapine administration for 28 days increased body weight while treatment with agmatine from days 15 to 28 prevented the body weight gain induced by olanzapine without any alteration in food intake. Repeated agmatine treatment decreased the elevated feeding efficiency and adiposity index, as well as improved dysregulated lipid metabolism induced by olanzapine. Increased activity of fatty acid synthase (FAS) and decreased expression of carnitine palmitoyl transferase-1 (CPT-1) were detected in chronic olanzapine-treated rats. Although agmatine treatment did not alter FAS activity, it increased CPT-1 activity. It is possible that the inhibitory effect of agmatine on weight gain and adiposity might be associated with increased mitochondrial fatty acid oxidation and energy expenditure in olanzapine-treated rats. We suggest that agmatine can be explored for the prevention of obesity complications associated with chronic antipsychotic treatment.

Evidences for agmatine alterations in Aß1-42induced memory impairment in mice.

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.

Imidazoline binding sites mediates anticompulsive-like effect of agmatine in marble-burying behavior in mice.

Agmatine is a cationic amine formed by decarboxylation of l-arginine by the mitochondrial enzyme arginine decarboxylase and widely distributed in mammalian brain. Although the precise function of endogenous agmatine has been largely remained unclear, its exogenous administration demonstrated beneficial effects in several neurological and psychiatric disorders. This study was planned to examine the role of imidazoline binding sites in the anticompulsive-like effect of agmatine on marble-burying behavior. Agmatine (20 and 40mg/kg, ip), mixed imidazoline I1/α2 agonists clonidine (60µg/kg, ip) and moxonidine (0.25mg/kg, ip), and imidazoline I2 agonist 2- BFI (10mg/kg, ip) showed significant inhibition of marble burying behavior in mice. In combination studies, the anticompulsive-like effect of agmatine (10mg/kg, ip) was significantly potentiated by prior administration of moxonidine (0.25mg/kg, ip) or clonidine (30µg/kg,) or 2-BFI (5mg/kg, ip). Conversely, efaroxan (1mg/kg, ip), an I1 antagonist and idazoxan (0.25mg/kg, ip), an I2 antagonist completely blocked the anticompulsive-like effect of agmatine (10mg/kg, ip). These drugs at doses used here did not influence the basal locomotor activity in experimental animals. These results clearly indicated the involvement of imidazoline binding sites in anti-compulsive-like effect of agmatine. Thus, imidazoline binding sites can be explored further as novel therapeutic target for treatment of anxiety and obsessive compulsive disorders.

Agmatine attenuates chronic unpredictable mild stress induced behavioral alteration in mice.

Chronic stress exposure and resulting dysregulation of the hypothalamic pituitary adrenal axis develops susceptibility to variety of neurological and psychiatric disorders. Agmatine, a putative neurotransmitter has been reported to be released in response to various stressful stimuli to maintain the homeostasis. Present study investigated the role of agmatine on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alteration in mice. Exposure of mice to CUMS protocol for 28 days resulted in diminished performance in sucrose preference test, splash test, forced swim test and marked elevation in plasma corticosterone levels. Chronic agmatine (5 and 10 mg/kg, ip, once daily) treatment started on day-15 and continued till the end of the CUMS protocol significantly increased sucrose preference, improved self-care and motivational behavior in the splash test and decreased duration of immobility in the forced swim test. Agmatine treatment also normalized the elevated corticosterone levels and prevented the body weight changes in chronically stressed animals. The pharmacological effect of agmatine was comparable to selective serotonin reuptake inhibitor, fluoxetine (10mg/kg, ip). Results of present study clearly demonstrated the anti-depressant like effect of agmatine in chronic unpredictable mild stress induced depression in mice. Thus the development of drugs based on brain agmatinergic modulation may represent a new potential approach for the treatment of stress related mood disorders like depression.