BACKGROUND:Impairment of cholinergic neurotransmission is a defining neurochemical feature of Alzheimer's disease and is closely associated with altered synaptic function and cerebral energy metabolism. Although acetylcholine influences multiple stages of memory processing, the biological substrates supporting the expression of previously acquired recognition memory remain insufficiently characterized. OBJECTIVE:This study examined whether acute antagonism of muscarinic acetylcholine receptors during the test phase of the novel object recognition (NOR) task alters retrieval performance and whether such behavioral effects are accompanied by changes in hippocampal brain-derived neurotrophic factor (BDNF) and glucose transporter-1 (GLUT-1). METHODS:Adult male SWR/J mice underwent NOR training and received intraperitoneal scopolamine (1 mg/kg) or saline 30 min before the test session. Recognition performance was quantified using discrimination index and object exploration measures. Hippocampal tissue was collected immediately after testing for Western blot analysis of BDNF and GLUT-1 expression. RESULTS:Muscarinic receptor blockade significantly reduced the ability of mice to preferentially explore the novel object, while total exploration time was increased versus controls. This behavioral deficit coincided with a decrease in hippocampal pro-brain-derived neurotrophic factor (pro-BDNF) and GLUT-1 protein levels. CONCLUSIONS:These data indicate that cholinergic modulation during recognition memory expression is associated with coordinated neurotrophic and metabolic alterations in the hippocampus. Effective retrieval depends on the integrity of molecular systems supporting plasticity and energy supply, and cholinergic dysfunction may compromise memory expression partly through reducing hippocampal pro-BDNF, providing a mechanistic framework relevant to early cognitive dysfunction in neurodegenerative disease.

Aluminum exposure has been implicated in neurodegenerative disorders, and aluminum-based nanoparticles exhibit greater neurotoxicity than bulk aluminum, highlighting the need to identify protective agents. Cinnamaldehyde, a major bioactive compound of cinnamon, has demonstrated neuroprotective effects in experimental models. The present study investigated whether cinnamaldehyde could attenuate cognitive deficits induced by aluminum oxide nanoparticles (ALNP) and examined the involvement of hippocampal MAPK signaling and neurotrophic pathways. Adult male Swiss mice received ALNP (10 mg/kg, oral gavage) alone or in combination with cinnamaldehyde (100, 200, or 300 mg/kg, i.p.) for five days. Novel object recognition memory was evaluated using the novel object recognition (NOR) test, and hippocampal levels of phosphorylated and total ERK and p38, as well as BDNF, were measured by western blotting. ALNP exposure impaired recognition memory and increased phosphorylation of ERK and p38 without altering total protein levels. Cinnamaldehyde improved cognitive performance in a dose-dependent manner, with significant effects observed at 300 mg/kg. Cinnamaldehyde administered alone (300 mg/kg) did not alter cognitive performance, indicating selective protection against ALNP-induced deficits. This effective dose normalized ERK and p38 phosphorylation and significantly increased hippocampal BDNF expression. Total exploration time did not differ between any groups, indicating that behavioral effects were not attributable to locomotor alterations. These findings suggest that ALNP-induced cognitive impairment is associated with stress-related activation of MAPK signaling, and that cinnamaldehyde mitigates these neurotoxic effects, possibly through restoration of kinase signaling balance and enhancement of neurotrophic support. Collectively, the results identify intracellular signaling dysregulation as a potential mechanism of nanoparticle-induced cognitive dysfunction and support cinnamaldehyde as a candidate warranting further investigation for mitigating aluminum nanoparticle neurotoxicity.

Research has indicated a strong link between exposure to aluminum (Al) and the development of Alzheimer’s disease (AD). Given the rising use of Al nanoparticles, which are far more neurotoxic than Al, it is noteworthy to investigate the possible protective properties of natural substances. Curcumin, an important component of turmeric, has demonstrated neuroprotective effects in some animal studies. The main objective of this study was to examine the protective effects of curcumin on the memory deficit induced by subcutaneous aluminum oxide nanoparticles (Al-NP) administration in mice. Additionally, considering the roles of the hippocampal brain-derived neurotrophic factor (BDNF) and Akt pathway in AD pathology, their levels were evaluated. Adult male Swiss mice (SWR/J) were administered Al-NP (10 mg/kg/s.c.) with or without curcumin (2.5, or 25 mg/kg/P.O) for 10 days. Memory and anxiety-like behavior were assessed using passive avoidance and elevated plus maze tasks, respectively. Western blot analysis was employed to measure hippocampal BDNF and Akt proteins in the hippocampus. The findings revealed that Al-NP induced memory impairment in mice, whereas curcumin at 25 mg/kg prevented this memory deficit. Additionally, Al-NP significantly reduced the hippocampal BDNF and phosphorylated Akt levels, while curcumin increased BDNF and phosphorylated Akt to a nonsignificant level compared to the control group. These results not only suggest the neuroprotective properties of curcumin but also suggest a possible association between hippocampal BDNF and Akt signaling in the neuroprotective mechanism of this compound against Al-NP toxicity.

Alzheimer’s disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined. This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms α and β, together with extracellular signal-regulated kinase (ERK) signaling. Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1 mg/kg, i.p.) or saline 30 min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-α, CaMKII-β, and ERK. Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-α and CaMKII-β while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase. These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (α and β) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-α) and structural (CaMKII-β) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.

BACKGROUND:Aluminum (Al) exposure has been implicated in neurodegenerative disorders, particularly Alzheimer's disease (AD). Due to their small size and increased bioavailability, Al oxide nanoparticles (Al-NP) exhibit greater neurotoxicity than bulk Al, leading to hippocampal damage, neuronal loss, and cognitive decline. This study investigates whether agmatine, a polyamine with neuroprotective properties, mitigates Al-NP-induced memory impairment and hippocampal neurodegeneration. METHODS:Male Swiss mice (SWR/J) were randomly assigned to four groups: Control, Al-NP (10 mg/kg, oral), Al-NP + Agmatine (5 mg/kg or 10 mg/kg, intraperitoneal). Cognitive function was assessed using the Novel Object Recognition (NOR) test. Stereological analysis quantified hippocampal volume, as well as the volume and cell number of the CA1 and dentate gyrus (DG) sub-regions. Apoptosis was evaluated via cleaved caspase-3, Bax, and Bcl-2 expression using western blot analysis. RESULTS:Al-NP exposure significantly impaired memory performance, reduced hippocampal volume, and induced atrophy and neuronal loss in CA1 and DG. Molecular analysis revealed elevated cleaved caspase-3 expression, increased Bax, decreased Bcl-2, and an elevated Bax/Bcl-2 ratio, indicating activation of intrinsic apoptosis. Agmatine (10 mg/kg) effectively restored memory function, preserved hippocampal structure, and normalized apoptotic markers, suggesting its neuroprotective role. CONCLUSION:Agmatine exerts potent neuroprotective effects against Al-NP-induced hippocampal toxicity by mitigating memory deficits, preventing neuronal loss, and suppressing apoptosis through downregulation of cleaved caspase-3 and modulation of Bax/Bcl-2 signaling. These structural and molecular changes may underlie its cognitive benefits. Given the role of hippocampal atrophy in AD, agmatine may be a promising candidate for preventing Al-related neurodegeneration and AD progression.

Aluminum (Al) exposure has been implicated in Alzheimer's Disease (AD) pathogenesis. Al nanoparticles (AlNPs) exhibit enhanced neurotoxicity compared to Al ions, posing a significant concern. Cinnamaldehyde (CNMA), a natural compound with neuroprotective properties, was investigated for its ability to mitigate AlNP-induced cognitive deficits and modulate underlying signaling pathways. Adult male Swiss mice were administered AlNPs (10 mg/kg, oral) alone or in combination with CNMA (100, 200, or 300 mg/kg, intraperitoneal) for 5 days. Cognitive function was assessed using the novel object recognition (NOR) test. Western blot analysis was employed to evaluate the expression levels of phosphorylated and total ERK and p38 proteins in the hippocampus. Results demonstrated that AlNP exposure significantly impaired cognitive function in mice, as evidenced by decreased discrimination index in the NOR test. Concomitantly, AlNP treatment led to an increase in phosphorylated ERK and p38 levels in the hippocampus, indicating activation of these signaling pathways. Notably, CNMA treatment, particularly at the 300 mg/kg dose, significantly ameliorated AlNP-induced cognitive deficits and attenuated the activation of both ERK and p38 signaling pathways. These findings suggest that CNMA exerts neuroprotective effects against AlNP-induced cognitive impairment, potentially through the modulation of ERK and p38 signaling pathways in the hippocampus. These results highlight the potential therapeutic implications of CNMA as a natural intervention for mitigating the neurotoxic effects of AlNPs.

Objectives: Exposure to aluminum (Al) has been shown to be strongly associated with the pathogenesis of Alzheimer's disease (AD). Recent evidence indicates that the toxicity of Al nanoparticle (Al-NP) is far greater than Al itself due to its particle size. Epidemiological studies suggest that curcumin lower the prevalence of AD. MAPKs (ERK, p38 and JNK) were suggested to be involved in AD pathology and memory impairment. The present study aimed to evaluate if curcumin has the ability to protect against behavioral deficits induced by subcutaneously administered Al-NP in mice. Furthermore, the levels of phosphorylated and total hippocampal MAPKs were assessed using western blottechnique.Methods: Al-NP (10 mg/kg/s.c.) was administered to adult male NMRI mice for 10 days with or without curcumin in doses of 2.5 or 25 mg/kg/oral gavage). Memory was assessed using passive avoidance apparatus and anxiety-like behavior was evaluated using elevated plus maze. Following the behavioral tasks, western blot analysis was performed on the hippocampal tissues to detect the levels of phosphorylated and total MAPKs.Results: The results revealed that Al-NP deteriorated memory with no significant effect on anxiety-like behaviors. Additionally, it activated hippocampal p38 signaling pathway with no effect on ERK and JNK. Curcumin treatment at the dose of 25 mg/kg restored memory and p38 activation.Discussion: This study suggests that subcutaneous Al-NP administration impairs memory and hippocampal p38 signaling with no effect on ERK and JNK. Co-administration of curcumin restored Al-NP induced memory impairment and hippocampal p38 phosphorylation.

Emerging evidence suggests a strong association between aluminum (Al) exposure and the development of Alzheimer's disease (AD). Due to their nanoscale size and increased surface area, Al nanoparticles (ALNP) exhibit greater neurotoxicity than bulk Al, raising concerns about their role in neurodegenerative disorders. While quercetin has been recognized for its neuroprotective effects, its ability to counteract ALNP-induced hippocampal neurodegeneration and dysregulated MAPK signaling remains largely unexplored. This study investigated the potential of quercetin to ameliorate ALNP-induced memory deficits, alterations in hippocampal stereological parameters, and disruptions in caspase-3 and MAPK signaling in male Swiss mice. Mice (SWR/J, aged 8-10 weeks) received ALNP (10 mg/kg, intraperitoneally for 10 days) with or without quercetin at doses of 1, 10, or 100 mg/kg (orally). Memory performance was assessed using the elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks, followed by stereological and western blot analyses of the hippocampus. Our findings revealed that quercetin (100 mg/kg) significantly preserved hippocampal volume and neuronal integrity in the dentate gyrus (DG) and Cornu Ammonis 1 (CA1)-key regions involved in memory processing and output signaling. Additionally, quercetin modulated MAPK signaling by enhancing ERK phosphorylation while suppressing ALNP-induced activation of p38 and cleaved caspase-3, suggesting a role in reducing neuroinflammation and apoptosis. This is the first study to demonstrate that quercetin can counteract the neurotoxic effects of ALNP, highlighting its potential as a therapeutic strategy against nanoparticle-induced neurodegeneration in an Alzheimer's-like model.

Memory impairment is a debilitating condition affecting millions worldwide, particularly the elderly. Alzheimer's disease, characterized by amyloid plaques and neurofibrillary tangles, is a major cause of dementia. Scopolamine, a muscarinic acetylcholine receptor antagonist, is commonly used to induce memory deficits in animal models. Curcumin, a natural polyphenol found in turmeric, has shown promise in improving cognitive function. In this study, we investigated the neuroprotective effects of nanocurcumin against scopolamine-induced memory impairment and its underlying mechanisms. The PI3K/Akt/GSK-3β signaling pathway plays a crucial role in neuronal survival and memory. Adult male mice were randomly assigned to different groups. Memory function was assessed using novel object recognition and Y-maze tasks. Western blot analysis was used to evaluate the expression levels of phosphorylated Akt and GSK-3β in the hippocampus. Scopolamine administration induced memory impairment, while pretreatment with nanocurcumin (2.5 mg/kg) prevented this deficit. Furthermore, scopolamine significantly decreased the ratio of phosphorylated to total Akt and reduced the phosphorylation of GSK-3β. Nanocurcumin treatment significantly reversed these effects. In contrast, natural curcumin at the same dose did not show any protective effects. Our findings suggest that nanocurcumin can effectively ameliorate scopolamine-induced memory impairment by activating the Akt/GSK-3β signaling pathway in the hippocampus. This study highlights the potential of nanocurcumin as a therapeutic agent for cognitive disorders.

Aluminum (Al) exposure has been linked to Alzheimer's Disease (AD) pathogenesis. Al nanoparticles (AlNPs) exhibit significantly higher neurotoxicity compared to Al ions. Curcumin, a natural compound with neuroprotective properties, was investigated for its ability to mitigate AlNP-induced cognitive impairment. Adult male Swiss mice were administered AlNPs (10 mg/kg, subcutaneous) alone or in combination with curcumin (2.5 or 25 mg/kg, oral) for 10 days. Cognitive function was assessed using the passive avoidance test, while anxiety-like behavior was evaluated using the elevated plus maze. Western blot analysis was employed to evaluate the expression levels of BDNF and phosphorylated Akt in the hippocampus. Results demonstrated that AlNP exposure significantly impaired cognitive function in mice, while curcumin treatment, particularly at 25 mg/kg, significantly ameliorated this impairment. AlNP treatment significantly decreased hippocampal BDNF and phosphorylated Akt levels, indicating a downregulation of the BDNF-Akt signaling pathway. Notably, curcumin treatment significantly increased BDNF and phosphorylated Akt levels compared to the AlNP-treated group, suggesting an enhancement of this neuroprotective pathway. These findings suggest that curcumin exerts neuroprotective effects against AlNP-induced cognitive impairment, potentially through the enhancement of BDNF-Akt signaling in the hippocampus. These results highlight the potential therapeutic implications of curcumin as a natural intervention for mitigating the neurotoxic effects of AlNPs.

The central route of streptozotocin (STZ) administration has been introduced as a rat model of sporadic Alzheimer 's disease (AD). Curcumin was suggested to possess possible neuroprotective effects, which may be profitable in AD. However, the low bioavailability of curcumin hinders its beneficial effects in clinical studies. Earlier studies suggested that a bovine serum albumin-based nanocurcumin, produces superior neuroprotective effects compared to natural curcumin. In the present study, the protective effect of nanocurcumin in rat model of central STZ induced memory impairment was assessed. In addition, due to the importance of the hippocampus in memory, the amounts of hippocampal active caspase-3, Akt, and CaMKII- alpha were evaluated. Adult male Wistar rats weighing 250 -300 g were used. STZ (icv) was injected during days 1 and 3 (3 mg/kg in divided), and nanocurcumin or curcumin 50 mg/kg/oral gavage was administered daily during days 4 -14. Morris water maze training was performed on days 15 -17, and the retention memory test was achieved on the 18th day. Following memory assessment, the rats were sacrificed and the hippocampi were used to assess caspase-3 cleavage, Akt, and CaMKII- alpha signaling. The findings revealed that nanocurcumin ingestion (but not natural curcumin) in the dose of 50 mg/kg was capable to prevent the impairment of water maze learning and memory induced by central STZ. Molecular assessments indicated that STZ treatment increased the caspase-3 cleavage in the hippocampus while deactivating Akt and CaMKII- alpha. Nanocurcumin reduced caspase-3 cleavage to a non-significant level compared to control group and restored Akt and CaMKII- alpha within the hippocampus while natural curcumin exerted no significant effect. These findings might suggest that nanocurcumin can restore memory deficit, hippocampal apoptosis as well as Akt and CaMKII- alpha signaling disruption associated with brain insulin resistance.

Objectives: Increasing evidence indicates a link between aluminum (Al) intake and Alzheimer's disease (AD). The main entry of Al into the human body is through oral route, and in the digestive tract, under the influence of the pH change, Al can be transformed into Al nanoparticles (Al-NP). However, studies related to the effect of Al-NP on the brain are limited and need further investigation. Neuro-inflammation is considered as one of the principal features of AD. Microglial activation and expression of the inflammatory cytokine IL-1 beta (interleukin-1 beta) in the brain have been used as hallmarks of brain inflammation. Therefore, in the present study, the hippocampal levels of ionized calcium-binding adaptor molecule 1 (IBA-1), as the marker of microglia activation, and IL-1 beta were assessed.Methods: Adult male NMRI mice were treated with Al-NP (5 or 10 mg/kg) for 5 days. A novel object recognition (NOR) test was used to assess memory. Following cognitive assessments, the hippocampal tissues were isolated to analyze the levels of IL-1 beta and IBA-1 as well as beta actin proteins using western blot technique.Results: Al-NP in both doses of 5 and 10 mg/kg impaired NOR memory in mice. In addition, Al-NP increased IL-1 beta and IBA-1 in the hippocampus.Discussion: These findings indicate that the memory impairing effect of Al-NP coincides with hippocampal inflammation. According to the proposed relationship between AD and Al toxicity, this study can increase the knowledge about the toxic effects of Al-NP and highlight the need to limit the use of this nanoparticle. [GRAPHICS]

Erythropoietin (EPO) has been considered in several studies as a significant factor in the development of erythroid cells, the inhibition of neuronal cell death, and neurogenesis. Fortunately, a modified version of EPO called carbamylated erythropoietin (CEPO) possesses tissue-protective properties without eliciting erythropoietic effects. CEPO is a derivative of EPO that results in an alpha-amino derivative group with less biological hematopoiesis than EPO. In neurological diseases, CEPO and its carbamylated erythropoietin Fc fusion protein (CEPO-Fc) has been shown to play a better role than EPO. In this study, the effects of EPO and its derivatives on neurological diseases and their role in treatment have been reviewed.

ABSTRACT Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII-α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII-α signaling. In addition, the effect of sub-chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII-α deregulation was investigated in mice. Adult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII-α and beta actin proteins. The results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII-α. Sub-chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII-α. This study suggests that hippocampal CaMKII-α might play a role in scopolamine induced amnesia and sub-chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII-α protein. GRAPHICAL ABSTRACT

Most published studies identify groundwater extraction as the leading cause of land subsidence (LS). However, the causes of LS are not only attributable to groundwater extraction. Other land-use practices can also affect the occurrence of LS. In this study, radar interferometric techniques and machine learning (ML) models were used for the prediction, susceptibility zoning, and prioritization of influential variables in the occurrence of LS in the Bakhtegan basin. The LS rate was characterized by applying an interferometric synthetic aperture radar (InSAR). The recursive feature elimination (RFE) method was used to detect and select the dominant combination of indicators to prepare an LS susceptibility map. Three ML models, including random forest (RF), k-nearest neighbors (KNN), and classification and regression trees (CART), were used to develop predictive models. All three models had acceptable performance. Among the ML models, the RF model performed the best (i.e., Nash–Sutcliffe efficiency, Kling–Gupta efficiency, correlation coefficient, and percent bias metrics of 0.76, 0.78, 0.88, and 0.70 for validating phase, respectively). The analysis conducted on all three ML model outputs showed that high and very high LS susceptibility classes were located on or near irrigated agricultural land. The results indicate that the leading cause of land LS in the study region is not due to groundwater withdrawals. Instead, the distance from dams and the proximity to anticlines, faults, and mines are the most important identifiers of LS susceptibility. Additionally, the highest probability of LS susceptibility was found at distances less than 18 km from synclines, 6 to 13 km from anticlines, 23 km from dams, and distances less than 20 to more than 144 km from mines. The validated methods presented in this study are reproducible, transferrable, and recommended for mapping LS susceptibility in semiarid and arid climate zones with similar environmental conditions.

Although, both environmental and genetic factors are known as the predispositions to AD development, each of these factors are suggested to acts via increasing the Al content of brain tissue. Al nanoparticles are newer nanomaterials that have been significantly exposed to the human body. When Al reaches the nanosize, it may display different characteristics from natural Al, and its potential influence on body function is an interesting aspect of research as these particles might have more negative impact on human health. Activation of microglia and expression of the inflammatory cytokine IL‐1 (interleukin‐1) in the brain have been used as hallmarks of brain inflammation. Our recent findings suggest that administration of nano‐Al for a short period of 5 days can cause memory impairment. Given the importance of neuroinflammation in Alzheimer’s pathology, the question was whether 5‐day nano‐Al intake could lead to inflammatory changes in the hippocampus.

The growing usage of aluminum nanoparticles (Al-NP) and their exposure may influence body function. Considering the proposed relationship between Al and the pathogenesis of Alzheimer’s disease and the concern about the effect of this nanoparticle on brain health and cognitive function, the use of neuroprotective agents might be helpful. According to the reported neuroprotective effects of agmatine, in the present study, the possible protective effect of agmatine was assessed in mice model of Al-NP-induced memory impairment. In addition, due to the roles of hippocampal Glycogen synthase kinase-3 beta (GSK-3β) and ERK signaling in memory and its disorders, these pathways were also investigated. Al-NP (10 mg/kg/p.o.) with/without agmatine (5 or 10 mg/kg/i.p.) was administered to adult male NMRI mice for 5 days. Novel object recognition (NOR) test session was used to assess cognitive function. Following the behavioral assessments, the hippocampi were used to determine the phosphorylated and total levels of GSK-3β and ERK as well as GAPDH using western blot analysis. The results showed that Al-NP impaired NOR memory in mice while agmatine 10 mg/kg prevented the memory deficit induced by Al-NP. Furthermore, Al-NP activated GSK-3β as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3β and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3β and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

Agmatine is a polyamine suggested to act as a supposed neurotransmitter in the brain. Evidence has indicated that acute agmatine administration might modulate memory. The present study aimed to investigate the effect of repeated agmatine treatment on passive avoidance memory, hippocampal calcium-calmodulin-dependent protein kinase II-alpha (CaMKII-alpha), and Extracellular Signal-Regulated Kinase (ERK) signaling pathways in naive mice. Adult male NMRI mice were treated with agmatine (10, 20, 30, 40, and 80 mg/kg/ip) or saline for 11 days. Acquisition and retention tests of passive avoidance memory were performed on days 10 and 11, respectively. Following the memory retention test, the hippocampi were assessed for the levels of CaMKII-alpha and ERK using the western blotting technique. The results revealed the dose-dependent effect of agmatine on the passive avoidance memory. Accordingly, the memory was impaired in lower doses, but was improved in higher ones. Agmatine in none of the doses affected the nociception of the mice in tail-flick test. Furthermore, agmatine increased the phosphorylation of CaMKII-alpha and ERK in the hippocampus at memory enhancing doses, while ERK phosphorylation decreased following the impairing doses of agmatine. Thus, the dose-dependent effect of agmatine on memory might be related to its modulatory effect on CaMKII-alpha and ERK signal transduction, eventually regulating the memory process.