Agmatine as a novel candidate for rapid-onset antidepressant response

Abstract

Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

m6A Regulator-Mediated RNA Methylation Modification Patterns are Involved in the Pathogenesis and Immune Microenvironment of Depression

“…Depression is a crippling and highly prevalent emotional disorder and the leading cause of suicide ( Valverde et al, 2021 ). With an increase in life stress and social pressure, the prevalence and incidence of depression is increasing globally ( Guo et al, 2020 ).…”

New Insights into Identification, Distribution, and Health Benefits of Polyamines and Their Derivatives

“…Numerous investigations have documented the therapeutic efficacy of agmatine on diverse neurological disorders, notably encompassing the treatment of conditions such as depression, anxiety, neuropathic pain, cognitive and learning impairments, as well as drug dependence. ,, Agmatine, functioning as a neuromodulator, orchestrates the regulation of multiple neurotransmitters and signaling pathways. Numerous investigations unravel the intricate mechanisms. ,, This neuroprotection appears to be facilitated through mitigation of oxidative damage, suppression of neuroinflammation, and modulation of proapoptotic signaling. ,, Moreover, concerning the therapeutic impact of agmatine on neurological diseases with a specific focus on ion channels and receptors, an additional review has been disseminated . Given that these processes are implicated in disorders associated with acute and chronic excitotoxicity, such as ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative conditions, and psychiatric disorders, as well as in nociception, agmatine emerges as a promising therapeutic approach for central nervous system disorders .…”

“…Numerous investigations have documented the therapeutic efficacy of agmatine on diverse neurological disorders, notably encompassing the treatment of conditions such as depression, anxiety, neuropathic pain, cognitive and learning impairments, as well as drug dependence. 111,125,126 Agmatine, functioning as a neuromodulator, orchestrates the regulation of multiple neurotransmitters and signaling pathways. Numerous investigations unravel the intricate mechanisms.…”

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

“…Agmatine has been colocalized with other neurotransmitters, notably glutamate in synaptic terminals in hippocampal CA1 region ( Seo et al, 2011 ). It also binds with high affinity several postsynaptic membrane receptors, such as α2-adrenergic receptors, imidazoline I1 and I2 receptors, nicotinic receptors and serotoninergic 5HT-2A and 5HT-3 receptors, and blocks glutamate NMDA receptor channels in a similar way as the rapid-acting antidepressant ketamine ( Yang and Reis, 1999 ; Reis and Regunathan, 2000 ; Halaris and Piletz, 2007 ; Uzbay, 2012 ; Neis et al, 2016a , b , 2018 ; Barua et al, 2019 ; Camargo and Rodrigues, 2019 ; Valverde et al, 2021 ). Moreover, agmatine is a key modulator of nitric oxide and polyamine overproduction during the “Polyamine Stress Response” that is important for proper adaptive responses of quiescent cells to stressful conditions ( Piletz et al, 2013 ).…”