Perspectives on Agmatine Neurotransmission in Acute and Chronic Stressrelated Conditions

Abstract

Adaptive responses to stressful stimuli in the environment are believed to restore homeostasis after stressful events. Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases glucocorticoids (GCs) into the bloodstream. Recently, agmatine, an endogenous monoamine, was discovered to have the potential as a pharmacotherapy for stress. Agmatine is released in response to certain stress conditions, especially those involving GCs, and participates in establishing homeostasis disturbed by stress during stress following GC activation. The therapeutic potential of agmatine for the management of psychological diseases involving stress and depression is promising based on a significant amount of literature. When exogenously applied, agmatine leads to reductions in levels of GCs and counteracts stress-related morphologic, synaptic, and molecular changes. However, the exact mechanism of action by which agmatine modifies the effects resulting from stress hormone secretion is not fully understood. This review aims to present the most possible mechanisms by which agmatine reduces the harmful effects of chronic and acute stress. Several studies suggest chronic stress exposure and repeated corticosteroid treatment lower agmatine levels, contributing to stress-related symptoms. Agmatine acts as an antistress agent by activating mTOR signaling, inhibiting NMDA receptors, suppressing iNOS, and maintaining bodyweight by activating α-2adrenergic receptors. Exogenous administration that restores agmatine levels may provide protection against stress-induced changes by reducing GCs release, stimulating anti-inflammatory processes, and releasing neuroprotective factors, which are not found in all therapies currently being used to treat stress-related disorders. The administration of exogenous agmatine should also be considered a therapeutic element that is capable of triggering a neural protective response that counters the effects of chronic stress. When combined with existing treatment strategies, this may have synergistic beneficial effects.

Preventive putative effect of agmatine on cognitive and molecular outcomes in ventral tegmental area of male offspring following physical and psychological prenatal stress

“…Considering that several previous studies have indicated that PS might differentially affect each sex (Gué et al., 2004; GhotbiRavandi et al., 2021), the sex‐dependent effects of PS must be taken into account. The findings of our present study are comparable to our recent findings in female offspring (Hassanshahi et al., 2023). Similar to what we observed in the male offspring, PS resulted in impaired locomotor activity, increased anxiety‐like behavior, heightened drug‐seeking behavior, and impaired passive avoidance memory in the female offspring, which were prevented with the administration of agmatine during the pregnancy (Hassanshahi et al., 2023).…”

“…The findings of our present study are comparable to our recent findings in female offspring (Hassanshahi et al., 2023). Similar to what we observed in the male offspring, PS resulted in impaired locomotor activity, increased anxiety‐like behavior, heightened drug‐seeking behavior, and impaired passive avoidance memory in the female offspring, which were prevented with the administration of agmatine during the pregnancy (Hassanshahi et al., 2023). Moreover, our findings indicate that PS had no detrimental effects on hippocampal BDNF both in male and female offsprings.…”

Administration of agmatine prior to physical or psychological stress in pregnant mice ameliorates behavioural and cognitive deficits in female offspring

“…Furthermore, it has been reported that agmatine possesses antidepressive (Neis et al, 2016), anxiolytic (Gawali et al, 2017), antinociceptive (Kotagale et al, 2013) and anti‐inflammatory (Kim et al, 2016) properties. Agmatine has also proven to be a protective agent against chronic unpredictable stress‐induced behavioural and cognitive deficits (Gawali et al, 2017; Taksande et al, 2013), which involved inhibition of NMDA receptors as well as activation of BDNF signalling (Gawali et al, 2017; Hassanshahi et al, 2023).…”

“…Agmatine binds with high affinity to α2-adrenoceptors and imidazoline binding sites, as well as being an antagonist of the N-methyl-D-aspartate (NMDA) receptor and a competitive inhibitor of nitric oxide synthase (NOS) (Gawali et al, 2017). Studies have revealed that agmatine is implicated in the physiological response to stress as well as its associated disorders (for review, see Hassanshahi et al, 2023). Following investigations of effects of agmatine in various neurological and neuropsychiatric disorders, evidence has emerged suggesting a potential of agmatine as a neuroprotective agent.…”

Glucocorticoids in lung cancer: Navigating the balance between immunosuppression and therapeutic efficacy

“…The effects of GCSs on mediators of inflammation and immune responses include: (i) reducing the production of prostaglandin compounds by decreasing the expression of cyclooxygenase II and inhibiting the release of arachidonic acid substrates [ 153 ]; (ii) decreasing the production of numerous cytokines, including TNF-α, cell adhesion molecules, IL-1, IL-3, IL-2, IL-4, IL-6, IL-5, IL-8, and granulocyte-macrophage colony-stimulating factor, largely secondary to the inhibition of gene transcription [ 154 ]; (iii) lowering the concentration of complement components in plasma [ 155 ]; (iv) reducing the production of NO by inducing the production of nitric oxide synthase 2 (NOS2) isoforms [ 156 ]; (v) decreasing the release of histamine and other mediators from basophils and mast cells [ 157 ]; (vi) reducing the production of immunoglobulin G (IgG) [ 158 ]; (vii) increasing the synthesis of anti-inflammatory factors such as IL-10, IL-1 soluble receptor, and clusterin [ 159 ]; (viii) endogenous GCs entering the bloodstream increase in quantity during inflammation and stress events [ 160 ], playing a crucial regulatory role in preventing excessive activation of inflammation and other potent defense responses, which, if left uncontrolled, may lead to a state of dysregulation in the organism [ 161 ].…”