Endogenous Agmatine Induced by Ischemic Preconditioning Regulates Ischemic Tolerance Following Cerebral Ischemia

Abstract

Ischemic preconditioning (IP) is one of the most important endogenous mechanisms that protect the cells against ischemia-reperfusion (I/R) injury. However, the exact molecular mechanisms remain unclear. In this study, we showed that changes in the level of agmatine were correlated with ischemic tolerance. Changes in brain edema, infarct volume, level of agmatine, and expression of arginine decarboxylase (ADC) and nitric oxide synthases (NOS; inducible NOS [iNOS] and neural NOS [nNOS]) were analyzed during I/R injury with or without IP in the rat brain. After cerebral ischemia, brain edema and infarct volume were significantly reduced in the IP group. The level of agmatine was increased before and during ischemic injury and remained elevated in the early reperfusion phase in the IP group compared to the experimental control (EC) group. During IP, the level of plasma agmatine was increased in the early phase of IP, but that of liver agmatine was abruptly decreased. However, the level of agmatine was definitely increased in the ipsilateral and contralateral hemisphere of brain during the IP. IP also increased the expression of ADC—the enzyme responsible for the synthesis of endogenous agmatine—before, during, and after ischemic injury. In addition, ischemic injury increased endogenous ADC expression in the EC group. The expression of nNOS was reduced in the I/R injured brain in the IP group. These results suggest that endogenous increased agmatine may be a component of the ischemic tolerance response that is induced by IP. Agmatine may have a pivotal role in endogenous ischemic tolerance.

Restorative Mechanism of Neural Progenitor Cells Overexpressing Arginine Decarboxylase Genes Following Ischemic Injury

“…In this study, we confirmed that the exogenously transfected by retrovirus delivery vehicle containing human ADC gene is efficiently introduced stable, heritable genetic material into the host genome of neural stem cells and mesenchymal stem cells [1420]. We also confirmed that the endogenous ADC expression is increased in the wild-type cells and normal brain tissue in the previous study [14204445] and the present study. Nevertheless, in the further increase of ADC expression after ischemic injury, it is difficult to differentiate between the effect of ADC gene delivery and the endogenous increase in response to stress.…”

Role of agmatine in the application of neural progenitor cell in central nervous system diseases: therapeutic potentials and effects

“…There is evidence to suggest that agmatine can be characterized as an inhibitory subunit for monoamide oxidase, an important neurotransmitter regulator, when administered in high concentrations (167M) [ 29 ]. NOS has been shown to be competitively inhibited by agmatine in vitro , which has a substantial impact on the function and actions of agmatine in the mammalian brain [ 17 , 30 - 32 ].…”

“…Both endogenous and exogenous agmatine can exert their functions on NO and reduce ischemic brain injury in neonatal rats, levels of both are also increased during ischemic insults [ 33 , 34 ]. Kim et al [ 32 ] demonstrated the neuroprotective functions of agmatine, both in vivo and in vitro through reducing the production of NO by competitively inhibiting neuronal NOS (nNOS) and isoform NOS (iNOS). ADC is localized in astrocytes, so endogenous agmatine production is thought to be predominantly in astrocytes which are mainly absent in in vivo studies involving cultured neurons.…”

Maintenance of the Neuroprotective Function of the Amino Group Blocked Fluorescence-Agmatine

“…In this condition, the sustained higher level of NO opens the N-methyl-d-aspartate (NMDA) channels through which the calcium influxes, causing neurotoxicity. After several hours of injury, the ADC/agmatine level increases and controls the iNOS and NMDA receptor functions [12,13]. In addition to ischemic or traumatic injury, agmatine has been found to have a positive effect on neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and other mental diseases [14][15][16].…”