Wonseok Chang; Jihua An; Sang Hyun Jang; Moonil Kim; Sun Seek Min

doi:10.4196/kjpp.24.399

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Chang, An, Jang, Kim, and Min: Agmatine decreases long-term potentiation via α2-adrenergic receptor and imidazoline type 1 receptor in the hippocampus

Original Article

Korean J. Physiol. Pharmacol. 2025;29(5):593-601.

Published online: 1 September 2025

DOI: https://doi.org/10.4196/kjpp.24.399

Agmatine decreases long-term potentiation via α2-adrenergic receptor and imidazoline type 1 receptor in the hippocampus

Wonseok Chang^1,^#, Jihua An^1,^#, Sang Hyun Jang², Moonil Kim³, Sun Seek Min^1,^*

¹Department of Physiology and Biophysics, Eulji University School of Medicine, Daejeon 34824, Korea

²Department of Neurology, Eulji University Hospital School of Medicine, Eulji University, Daejeon 35233, Korea

³Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea

^*Correspondence Sun Seek Min, E-mail: ssmin@eulji.ac.kr

Equal contributor:

^# These authors contributed equally to this work.

Contributed by:

Author contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept, design, supervision: S.S.M. Acquisition and analysis of data and original draft: J.A. Writing-review & editing: W.C., M.K., S.H.J., and S.S.M.

Received 6 December 2024 Revised 7 May 2025 Accepted 9 June 2025

(open-access):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Agmatine, a decarboxylation product of L-arginine, has been proposed as a novel neurotransmitter/neuromodulator with diverse neuroprotective and antidepressant-like effects. Although its therapeutic potential has been explored, the precise mechanisms by which agmatine modulates synaptic transmission and plasticity in the hippocampus remain unclear. In this study, we investigated the effects of agmatine on the induction and maintenance of long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices, its ability to counteract amyloid-β (Aβ1-42)-induced LTP impairment, and the receptor systems involved. Bath application of agmatine significantly suppressed the maintenance phase of LTP. Notably, agmatine reversed Aβ-induced deficits in LTP, suggesting a protective effect against synaptic dysfunction. Pharmacological experiments demonstrated that these effects were mediated via α2-adrenergic and imidazoline type I receptors. Paired-pulse facilitation and input–output analyses revealed that agmatine did not alter presynaptic release probability but selectively modulated postsynaptic transmission, particularly under AMPA receptor blockade, indicating a potential regulation of NMDA receptor-mediated signaling. Together, these findings suggest that agmatine modulates hippocampal synaptic plasticity through receptor-specific, postsynaptic mechanisms, and highlight its potential as a therapeutic agent against synaptic impairments in neurodegenerative diseases.

Keywords: Agmatine, Amyloid beta-peptides, Imidazoline receptors (I1 subtype), Long-term potentiation, Receptors, adrenergic, alpha-2, Synaptic plasticity

INTRODUCTION

Agmatine, a decarboxylation product of L-arginine and an intermediary of polyamine is inactivated by agmatinase, expresses in stomach, aorta, small intestine, large intestine, kidney, heart, brain etc. in mammals [1]. It is considered as a novel putative neurotransmitter/neuromodulator currently. Agmatine is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, released by membrane depolarization [2,3]. Recent research has illuminated the diverse effects of agmatine on the nervous system. Agmatine has the ability to block NMDA receptors, various forms of nicotinic receptors, and voltage-gated Ca²⁺ channels [4 -6]. These mechanisms suggest that agmatine may play an important role in neuroprotection. Studies have demonstrated its potential to mitigate damage induced by NMDA and glutamate receptors, prevent memory impairment and apoptosis, and inhibit nitric oxide synthase, contributing to its antidepressant-like effects. Notably, agmatine has shown efficacy in preventing memory deficits associated with Aβ25-35 in behavioral studies [7 -11].

Amyloid beta (Aβ) is a peptide of 39–43 amino acids that derived by proteolytic processing of amyloid precursor protein and it appears to be a pathologic hallmark in the brain of Alzheimer's disease (AD) patients [12]. Small, soluble oligomers of Aβ have been isolated from brain, hippocampus, plasma, cerebrospinal fluid, transfected cells, and cells derived from human brain [13 -17]. Numerous studies suggested that soluble, oligomeric Aβ assemblies were considered to affect neurotoxicity underlying synaptic dysfunction and neuron loss in AD [18,19].

A central synaptic mechanism by which Aβ diminishes cognitive functions is through the impairment of long-term potentiation (LTP) in the hippocampus [20 -23]. LTP is a long-lasting increase in signal transmission between two neurons, resulting from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity and it is widely considered one of the major cellular mechanisms of learning and memory [24,25]. Research has shown that Aβ administration activates NMDARs [19], and NMDA receptors modulate inflow of Na⁺ and Ca²⁺ and outflow of K⁺ in the postsynaptic component in synaptic plasticity [25]. Activation of NMDARs with Aβ administration resulting in excessive intracellular calcium ion influx, which inhibits LTP and reinforces long-term depression (LTD), thereby disrupting the balance of synaptic plasticity. Additionally, LTP inhibition has been observed in Alzheimer's model mice related with Aβ [26], underscoring the reduction of LTP as a critical synaptic-level mechanism in the pathophysiology of early AD.

Agmatine interacts with α2-adrenergic and imidazoline receptors. Adrenoceptors are a class of G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline (norepinephrine) and adrenaline (epinephrine). α and _β are two main groups of adrenoceptors. In addition, there are two subtypes of α receptor, α1 and α2. α1-adrenergic receptor mainly involves smooth muscle contraction. It causes vasoconstriction in many blood vessels including those of the skin, gastrointestinal system, kidney and brain [27]. α2-adrenergic receptor has ability of inhibition of insulin release in pancreas. Some studies showed it did positive effect on learning and memory in rat, when α2-adrenergic receptor was blocked [28,29].

There are three main imidazoline receptors: type 1, type 2 and type 3. Imidazoline type 1 receptor, mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure and it may belong to the neurocytokine receptor family, since its signaling pathways are similar to those of interleukins [12,30]. Imidazoline type 2 receptor is an important allosteric binding site of monoamine oxidase. Imidazoline type 3 receptor regulates insulin secretion from pancreatic beta cells [12].

Recent findings have suggested that α1-adrenergic receptors may facilitate synaptic plasticity by enhancing NMDA receptor activity and intracellular calcium signaling, thereby supporting LTP induction [31,32]. Moreover, imidazoline type 1 receptors, although less studied in the context of synaptic plasticity, are expressed in the hippocampus and have been implicated in the modulation of neuronal excitability and glutamatergic transmission [33]. These receptor systems may play complementary roles alongside α2-adrenergic receptors in mediating the effects of agmatine on hippocampal plasticity.

Despite the recognition that agmatine interacts with various molecules related to synaptic function and can help prevent memory loss caused by Aβ, its effects on hippocampal LTP have not been thoroughly investigated. Therefore, this study aims to explore the impact of agmatine on the induction and maintenance of LTP, assess its protective effects against Aβ-induced impairments in LTP, and elucidate the receptors involved in these processes.

METHODS

Hippocampal slice preparation and drug treatment

Hippocampal slices were prepared from 3- to 5-week-old C57BL/6NTacSam male and female mice. Mice were deeply anesthetized with Enflurane (Compound 347) and decapitated. All animal procedures were approved by the Institutional Animal Care and Use Committee of Eulji University (Approval No. EUIACUC 16-25). Brains were rapidly removed and placed in ice-cold, oxygenated (95% O2/5% CO₂) dissection solution. Brains were rapidly removed and placed in ice-cold, oxygenated (95% O₂/5% CO₂) dissection solution containing (in mM): 212.7 sucrose, 2.6 KCl, 1.23 NaH₂PO₄, 26 NaHCO₃, 10 dextrose, 3 MgCl₂, and 1 CaCl₂. Transverse hippocampal slices (400 μm thick) were obtained using a vibratome (Campden Instruments, HA 752-060). Slices were incubated in artificial cerebrospinal fluid (aCSF) at 35°C for one hour before recording. The aCSF composition was (in mM): 124 NaCl, 5 KCl, 1.25 NaH₂PO₄, 26 NaHCO₃, 10 dextrose, 1.5 MgCl₂, and 2.5 CaCl₂. During experiments, slices were continuously perfused with oxygenated aCSF at 2 ml/min and maintained at 37°C ± 1°C.

Agmatine, prazosin, efaroxan, idazoxan, and Bu 224 were purchased from Sigma-Aldrich and freshly prepared in aCSF on the day of the experiment. Aβ1-42 (American Peptide Company) was dissolved in 0.05 M Tris buffer and incubated at 37°C for 7 days to promote aggregation into oligomers prior to application. The NMDA receptor antagonist D-AP5 (50 μM) and the AMPA receptor antagonist CNQX (10 μM) were bath-applied as indicated. Agmatine (100 μM) was also bath-applied as specified.

Electrophysiological recording

Field excitatory postsynaptic potentials (fEPSPs) were recorded from the stratum radiatum of the CA1 region using glass microelectrodes (1–3 MΩ) filled with aCSF. Schaffer collateral fibers were stimulated using a bipolar tungsten electrode. The stimulation intensity was adjusted to evoke fEPSPs with an amplitude corresponding to 40%–50% of the maximal response. Baseline responses were recorded for at least 20 min before induction. LTP was induced using four episodes of theta burst stimulation (4TBS), each consisting of 10 bursts at 5 Hz, with each burst containing four pulses at 100 Hz. To assess presynaptic function, paired-pulse facilitation (PPF) was measured by delivering two consecutive stimuli at various inter-stimulus intervals (ISIs) (25, 50, 100, 200, 400, 1,000, and 2,000 ms). The paired-pulse ratio was calculated as the slope of the second fEPSP divided by the first. Input–output (I–O) relationships were analyzed by plotting fiber volley amplitude against fEPSP amplitude, rather than slope, under both CNQX and AP5 treatment conditions. This approach was used to ensure consistency in waveform comparison, as both AMPA and NMDA receptor blockade altered the rising phase kinetics of fEPSPs, making slope measurements less reliable.

Statistical analysis

The degree of synaptic potentiation was quantified as the percent change in fEPSP slope relative to baseline. I–O curves were generated by plotting fEPSP amplitudes against fiber volley amplitudes. All data were analyzed using IBM SPSS Statistics 21 (SPSS Inc.). Results are presented as mean ± SEM. Group differences were assessed using one-way ANOVA followed by Tukey’s honestly significant difference test. A p-value < 0.05 was considered statistically significant.

RESULTS

Effect of agmatine on basal synaptic transmission

To investigate the effect of agmatine on basal synaptic transmission, the author applied agmatine in aCSF solution following 20 min of stable baseline responses. The recording continued for 80 min. The bar graph on the right illustrates the averaged values from 78 to 80 min. Fig. 1 depicts the impact of agmatine on basal synaptic transmission, where agmatine at a concentration of 400 μM showed no effect. In contrast, 500 μM agmatine significantly altered basal synaptic transmission (control: 96% ± 1%, 400 μM agmatine: 96% ± 4.16%, 500 μM agmatine: 87% ± 0.55%) as shown in Fig. 1.

Effects of agmatine on induction of LTP

The effects of agmatine on the induction of LTP were investigated by examining its presence throughout the recording period and specifically during the application of theta burst stimulation (4TBS). fEPSPs were recorded for 180 min following 4TBS, with agmatine tested at concentrations of 50 μM, 100 μM, and 400 μM. Fig. 2A, B illustrates that the LTP in the presence of agmatine was depressed in a dose-dependent manner, with percent changes in EPSP slope measured at 178–180 min post-4TBS (control: 148% ± 4.16%, 50 μM agmatine: 124% ± 8.71%, 100 μM agmatine: 121% ± 6.17%, 400 μM agmatine: 92% ± 8.89%).

Furthermore, the acute effects of agmatine on LTP induction were assessed by applying agmatine during 4TBS and subsequently washing it out. The percent changes in EPSP slope observed at 58–60 min post-4TBS are depicted in Fig. 2C, D, indicating that the application of agmatine at 100 μM or 400 μM during 4TBS suppresses LTP magnitude (control: 164% ± 4.01%, 50 μM agmatine: 153% ± 5.43%, 100 μM agmatine: 140% ± 3.58%, 400 μM agmatine: 132% ± 3.37%).

Effects of agmatine on maintenance of LTP

To examine the effect of agmatine on the maintenance of LTP, it was applied in aCSF solution 25 min after 4TBS. The bar graph on the right represents the averaged values at 178–180 min following 4TBS. Fig. 3 demonstrates that agmatine (100 μM and 400 μM) depotentiates the magnitude of LTP induced by 4TBS in a dose-dependent manner (control: 148% ± 4.16%, 50 μM agmatine: 131% ± 11.20%, 100 μM agmatine: 117% ± 13.61%, 400 μM agmatine: 106% ± 6.99%).

Effects of agmatine on Aβ1-42-induced impairment of LTP

To examine the protective effect of agmatine against the impairment of LTP induced by Aβ1-42, agmatine was applied in aCSF solution at the beginning of the recording. fEPSPs were recorded for 180 min following the application of 4TBS. The bar graph on the right displays the averaged values observed at 178–180 min post-4TBS. Fig. 4 illustrates that Aβ1-42 depressed LTP induction following 4TBS. Agmatine at a concentration of 50 μM was administered at least 10 min prior to the application of 400 nM Aβ1-42, with fEPSP recordings continuing for 180 min after 4TBS. Fig. 4 demonstrates that agmatine prevents the impairment of LTP induced by Aβ1-42 (control: 148% ± 4.16%, 400 nM Aβ1-42: 128% ± 4.95%, 400 nM Aβ1-42 + 50 μM agmatine: 143% ± 13.45%).

Agmatine's effects on LTP mediated by α1-adrenergic and imidazoline type 1 receptors

Bu 224, an imidazoline type 2 receptor antagonist, was applied at least 10 min before agmatine, and the recording of fEPSPs lasted for 180 min following 4TBS (Fig. 5). The bar graph on the right represents the averaged values observed at 178–180 min after 4TBS. Fig. 5A, B demonstrates that the effects of agmatine were not blocked by the imidazoline type 2 receptor antagonist (control: 148% ± 4.16%, 100 μM agmatine: 121% ± 6.17%, 100 μM agmatine + 10 μM Bu 224: 117% ± 10.22%).

Idazoxan, an α2-adrenergic receptor and imidazoline type 2 receptor antagonist, was also applied at least 10 min before agmatine, with fEPSP recordings lasting for 180 min after 4TBS. Fig. 5C, D illustrates that the effects of agmatine were not inhibited by idazoxan (control: 148% ± 4.16%, 100 μM agmatine: 121% ± 6.17%, 100 μM agmatine + 10 μM idazoxan: 121% ± 5.36%).

Efaroxan, an α2-adrenergic receptor and imidazoline type 1 receptor antagonist, was applied at least 10 min prior to the administration of agmatine. Fig. 5E, F shows that efaroxan blocks the effect of agmatine on LTP induction. Since idazoxan (α2-adrenergic receptor and imidazoline type 2 receptor antagonist) did not block the effect of agmatine on LTP induction, it can be presumed that agmatine binds to the imidazoline type 1 receptor to influence synaptic plasticity (control: 148% ± 4.16%, 100 μM agmatine: 121% ± 6.17%, 100 μM agmatine + 10 μM efaroxan: 136% ± 2.81%).

Subsequently, prazosin, an α1-adrenergic receptor antagonist, was administered at least 10 min prior to agmatine. Fig. 5G, H indicates that prazosin blocks the effect of agmatine on LTP induction. Therefore, it can be inferred that agmatine interacts with the α1-adrenergic receptor to modulate synaptic plasticity (control: 148% ± 4.16%, 100 μM agmatine: 121% ± 6.17%, 100 μM agmatine + 1 μM prazosin: 144% ± 7.65%).

Effects of agmatine on presynaptic function and synaptic transmission efficiency

To examine whether agmatine affects presynaptic function or basal synaptic transmission, PPF and I–O analyses were conducted. PPF was measured at ISIs of 25, 50, 100, 200, 400, 1,000, and 2,000 ms before and after agmatine treatment (100 μM). As shown in Fig. 6A, B, no significant difference was observed in PPF ratios across all ISIs following agmatine application, suggesting that agmatine does not influence presynaptic neurotransmitter release probability. To assess postsynaptic effects, I–O relationships were analyzed by plotting fiber volley amplitude against fEPSP amplitude. Under control conditions, agmatine did not significantly alter the I–O curve (Fig. 6C, D). In the presence of the NMDA receptor antagonist AP5 (50 μM), agmatine also failed to produce a significant change in the I–O relationship (Fig. 6E, F). However, when AMPA receptors were blocked by CNQX (10 μM), agmatine application significantly reduced the fEPSP amplitude across a range of fiber volley amplitudes (Fig. 6G, H; p < 0.05), indicating that agmatine suppresses synaptic responses mediated by NMDA receptors or other postsynaptic components in the absence of AMPA signaling. These findings suggest a receptor- and context-dependent postsynaptic modulation by agmatine.

DISCUSSION

This study investigated the effects of agmatine on the induction and maintenance of long-term synaptic plasticity in the hippocampal CA1 region. The findings revealed that agmatine inhibits the induction and the maintenance of LTP in a dose-dependent manner. These effects appear to be mediated through α1-adrenergic receptors and/or imidazoline type 1 receptors. Moreover, agmatine demonstrated a protective effect by preventing the impairment of LTP induction caused by Aβ, highlighting its potential protective role in synaptic plasticity.

The data confirmed that agmatine effectively depressed LTP induction and maintenance. To explore the mechanism, we assessed whether agmatine affects presynaptic release or postsynaptic responses. PPF analysis showed no significant difference across a range of ISIs, suggesting that agmatine does not alter presynaptic neurotransmitter release probability. However, I–O analysis revealed that agmatine significantly reduced fEPSP amplitude in the presence of CNQX, an AMPA receptor antagonist, while no significant change was observed under NMDA receptor blockade (AP5). These findings indicate that agmatine may modulate postsynaptic transmission, particularly under receptor-specific conditions where AMPA-mediated signaling is suppressed. Therefore, the inhibitory effects of agmatine on LTP are likely attributable to postsynaptic mechanisms.

One plausible explanation is that agmatine interferes with intracellular calcium signaling by blocking NMDA receptors and voltage-gated calcium channels [4 -6]. Previous studies have shown that 100 μM agmatine reduces NMDA currents by approximately 40% in hippocampal neurons [34,35]. Given that NMDA receptor activation is essential for the calcium influx that triggers LTP induction and cAMP response element-binding protein (CREB)-mediated transcription required for its maintenance [36,37], agmatine's inhibition of these calcium pathways could account for its suppressive effect on synaptic plasticity.

Interestingly, although agmatine inhibits LTP on its own, it also restored LTP impaired by Aβ1–42. This may appear paradoxical, but it highlights agmatine’s complex regulatory role in synaptic plasticity. Aβ is known to enhance NMDA receptor activation and promote excessive calcium influx, leading to synaptic toxicity and a shift from LTP to LTD [19,20,38]. By partially suppressing NMDA receptor overactivation, agmatine may restore calcium signaling to physiological levels, thus rebalancing synaptic plasticity towards LTP. This context-dependent modulation suggests that agmatine acts as a homeostatic regulator of calcium-dependent plasticity processes, providing neuroprotection against Aβ-induced dysregulation [39,40]. Although our results suggest that agmatine may modulate synaptic plasticity via NMDA receptor-mediated mechanisms, we did not directly investigate antioxidant activity or changes in synaptic protein expression. These possibilities remain open and warrant further investigation in future studies.

Our pharmacological data also support the involvement of specific receptor systems. Efaroxan (α2-adrenergic and imidazoline type 1 receptor antagonist) and prazosin (α1-adrenergic receptor antagonist) blocked agmatine's effect on LTP, while Bu 224 (imidazoline type 2 antagonist) and idazoxan (α2-adrenergic and imidazoline type 2 antagonist) did not. These results suggest that agmatine primarily exerts its effects through α1-adrenergic and imidazoline type 1 receptors. However, the lack of effect of idazoxan might be due to its known action as an agmatine uptake inhibitor [3,4], possibly enhancing agmatine’s concentration in the synaptic cleft. Additionally, prazosin, while selective for α1-adrenergic receptors, may also influence α2B- and α2C-subtypes [41], making it difficult to fully exclude α2-mediated contributions.

In summary, this study demonstrates that agmatine modulates synaptic plasticity through postsynaptic mechanisms involving α1-adrenergic and imidazoline type 1 receptors, and can prevent Aβ-induced LTP impairment. These findings support agmatine's potential as a therapeutic candidate for neurodegenerative diseases where synaptic dysfunction and excitotoxicity are prominent.

ACKNOWLEDGEMENTS

This manuscript is a revised version of Jihua An’s master’s thesis submitted to Eulji University.

Notes

FUNDING

This work was supported by EMBRI Grants 2019 (EMBRIDJ0004), Eulji University Research Grant 2021 (EJRG-21-17), the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2022R1I1A3073445), and the National Research Council of Science and Technology (NST) grant funded by the Korean government (CRC22021-300).

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

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Fig. 1

Agmatine concentration-dependent effects on basal synaptic transmission.

(A) After 20 min stable response, agmatine was applied in aCSF solution and perfused during time indicated by bar. Filled circle indicates control group. Open circle indicates 400 µM agmatine group, filled triangle means 500 µM agmatine group. (B) Panel B shows the percent change in fEPSP slope measured at 78–80 min relative to baseline (average of the 20-min pre-drug period). Values in parentheses indicate the number of animals and slices tested in each group. Data are presented as mean ± SEM. *p < 0.05, compared with control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. aCSF, artificial cerebrospinal fluid; agm, agmatine; fEPSP, field excitatory postsynaptic potential.

Fig. 2

Agmatine modulates long-term potentiation induction in a concentration-dependent manner.

(A) Agmatine was applied in aCSF at the beginning of the recording, which lasted for 180 min after four theta burst stimulation (4TBS). Field excitatory postsynaptic potentials (fEPSPs) were monitored for 180 min following 4TBS. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min relative to the baseline (average slope during the 20-min pre-4TBS period). Insets show representative traces recorded before (a) and 180 min after (b) 4TBS. (C) Agmatine was applied only during the 4TBS period and subsequently washed out. (D) Panel D shows percent changes in fEPSP slope measured at 58–60 min relative to baseline. In (A) and (B) panels, filled circles indicate the control group, open circles the 50 µM agmatine group, filled triangles the 100 µM agmatine group, and open triangles the 400 µM agmatine group. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01 compared to control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. aCSF, artificial cerebrospinal fluid.

Fig. 3

Agmatine suppresses LTP maintenance in a dose-dependent manner.

(A) Agmatine was applied in artificial cerebrospinal fluid (aCSF) following four theta burst stimulation (4TBS) and perfused during the period indicated by the horizontal bar. Field excitatory postsynaptic potentials (fEPSPs) were recorded throughout the experiment. Filled circle, open circle, filled triangle, open triangle indicate control group, 50 µM agmatine group, 100 µM agmatine group, 400 µM agmatine group, respectively. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min after 4TBS, relative to the baseline (average of the 20-min pre-4TBS period). Data are expressed as mean ± SEM. *p < 0.05 compared to control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. LTP, long-term potentiation.

Fig. 4

Agmatine restores LTP impairment induced by A

β. (A) Aβ1–42 (400 nM) was applied in artificial cerebrospinal fluid (aCSF) from the beginning of the recording. Field excitatory postsynaptic potentials (fEPSPs) were recorded for 180 min following four theta burst stimulation (4TBS). Agmatine (50 µM) was perfused in aCSF for at least 10 min prior to Aβ1–42 application. Filled circle, open circle, and open triangle represent the control group, 400 nM Aβ1-42 group, and 400 nM Aβ1–42 + 50 uM agmatine group respectively. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min relative to the baseline (average of the 20-min pre-4TBS period). Insets show representative traces recorded before (a) and 180 min after (b) 4TBS. Data are expressed as mean ± SEM. *p < 0.05 compared to Aβ-treated group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. LTP, long-term potentiation; Aβ, amyloid beta.

Fig. 5

Agmatine exerts its effects

via α1-adrenergic receptors and/or imidazoline type 1 receptors. Bu224 (10 µM), idazoxan (10 µM), efaroxan (10 µM), or prazosin (1 µM) was applied in artificial cerebrospinal fluid (aCSF) at least 10 min prior to the application of agmatine (100 µM). Field excitatory postsynaptic potentials (fEPSPs) were recorded for 180 min following four theta burst stimulation (4TBS). (A, C, E, G) show time-course changes in fEPSP slope under each pharmacological condition. Filled circles represent the control group, open circles the 100 µM agmatine group, and open triangles the group co-treated with agmatine and the respective antagonist (Bu224 in A, idazoxan in C, efaroxan in E, and prazosin in G). (B, D, F, H) show the percent changes in fEPSP slope measured at 178–180 min relative to baseline (average of the 20-min pre-4TBS period). Data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, n.s. = not significant; statistical comparisons were performed using one-way ANOVA followed by Tukey’s post- hoc test.

Fig. 6

Effects of agmatine on presynaptic function and postsynaptic synaptic transmission.

Paired-pulse facilitation (PPF) and input–output (I–O) analyses were conducted to evaluate presynaptic and postsynaptic effects of agmatine (100 µM). (A) Filled and open circles represent PPF responses before and after agmatine treatment, respectively, across inter-stimulus intervals of 25, 50, 100, 200, 400, 1,000, and 2,000 ms. (C) Filled and open circles indicate I–O curves obtained before and after agmatine treatment, respectively. (E) Filled and open circles represent responses in the presence of AP5 alone and AP5 + agmatine, respectively. (G) Filled and open circles indicate responses in the presence of CNQX alone and CNQX + agmatine, respectively. (B, D, F, H) Corresponding bar graphs show the area under the curve (AUC) values calculated from the respective I–O or PPF curves. AUC values were used for statistical comparison of synaptic response efficiency between conditions. Data are presented as mean ± SEM. *p < 0.05 was considered statistically significant. ISI, inter-stimulus interval; FV amp, fiber volley amplitude; fEPSP, field excitatory postsynaptic potential.

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