Cerebral venous thrombosis: a practical review.

The evolution of the Coronavirus Disease-2019 pandemic and its vaccination raised more attention to cerebral venous thrombosis (CVT). Although CVT is less prevalent than arterial stroke, it results in larger years of life lost. CVT is more common in women and young patients. Predisposing factors are categorized as transient factors such as pregnancy, puerperium, oral contraceptive pills, trauma, and dehydration; and permanent factors such as neoplastic, vasculitic, thrombophilic, hematologic conditions, infectious causes such as severe acute respiratory syndrome coronavirus-2 infection and HIV. The most common manifestations are headache, seizures, focal neurologic deficits, altered level of consciousness, and cranial nerve palsies. The most common syndromes are stroke-like, raised-intracranial-pressure (ICP), isolated-headache, and encephalopathy, which may have overlaps. Diagnosis is mostly based on computed tomography, magnetic resonance imaging, and their respective venous sequences, supported by blood results abnormalities such as D-dimer elevation. Treatment includes the prevention of propagation of current thrombus with anticoagulation (heparin, or low molecular weight heparinoids and then warfarin, or direct oral anticoagulants), decreasing ICP (even by decompressive craniotomy), and treatment of specific underlying diseases.

Combined use of hair follicle stem cells and CEPO (carbamylated erythropoietin)-Fc in a rat model of chronic cerebral hypoperfusion: A behavioral, electrophysiological, and molecular study.

BACKGROUND: In dementia, synaptic dysfunction appears before neuronal loss. Stem cell therapy could potentially provide a promising strategy for the treatment of dementia models. The carbamylated erythropoietin fusion protein (CEPO-Fc) has shown synaptotrophic effects. This study aimed to determine the efficiency of the combined use of hair follicle stem cells (HFSC) and CEPO-Fc in the basal synaptic transmission (BST) and long-term plasticity (LTP) of chronic cerebral hypoperfusion (CCH) rats. METHODS: We divided 64 adult rats into control, sham, CCH+vehicle, CCH+CEPO, CCH+HFSC, and CCH+HFSC+CEPO groups. The CEPO-Fc was injected three times/week for 30 days. HFSC transplantation was done on days 4, 14, and 21 after surgery. The Morris water maze test and passive avoidance were used to assess memory. BST and LTP were assessed by a field-potential recording of the CA1 region. The hippocampal mRNA expression of IGF-1, TGF-ß1, ß1-Catenine, NR2B, PSD-95, and GSk-3ß was evaluated by quantitative RT-PCR. RESULTS: Following combination therapy, spatial memory retention, and BST showed significant improvement relative to HFSC and CEPO-Fc groups. These effects were also confirmed by recovered mRNA expression of ß1-catenin, TGF-ß1, and NR2B. GSK-3ß expression was downregulated in all treatment groups. The upregulated PSD-95 was identified in HFSC and combination groups compared to the vehicle group. CONCLUSIONS: These findings indicate that the combined use of HFSC and CEPO-Fc may be more advantageous for treating memory disruption in the CCH model than CEPO-Fc or HFSC alone. This type of combination therapy may hopefully lead to a new approach to treatment for dementia.

Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke.

Although cell therapy has been applied in regenerative medicine for decades, recent years have seen greatly increased attention being given to the use of stem cell-based derivatives such as cell-free secretome. Dental pulp stem cells (DPSCs) are widely available, easily accessible, and have high neuroprotective and angiogenic properties. In addition, DPSC-derived secretome contains a rich mixture of trophic factors. The current investigation evaluated the short-term therapeutic effects of human DPSCs and their secretome in a rat model of mild ischemic stroke. Mild ischemic stroke was induced by 30 min middle cerebral artery occlusion, and hDPSCs or their secretome was administered intra-arterially and intranasally. Neurological function, infarct size, spatial working memory, and relative expression of seven target genes in two categories of neurotrophic and angiogenic factors were assessed three days after stroke. In the short-term, all treatments reduced the severity of neurological and histological deficits caused by ischemic stroke. Moreover, transient middle cerebral artery occlusion led to the striatal and cortical over-expression of BDNF, NT-3, and angiogenin, while NGF and VEGF expression was reduced. Almost all interventions were able to modulate the expression of target genes after stroke. The obtained data revealed that single intra-arterial administration of hDPSCs or their secretome, single intranasal transplantation of hDPSCs, or repeated intranasal administration of hDPSC-derived secretome was able to ameliorate the devastating effects of a mild stroke, at least in the short-term.

Transverse Myelitis as a Rare Neurological Complication of Coronavirus Disease 2019: A Case Report and Literature Review.

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is primarily a respiratory virus. However, an increasing number of neurologic complications associated with this virus have been reported, e.g., transverse myelitis (TM). We report a case of a 39-year-old man admitted to Namazi Hospital affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. In December 2020, the patient was infected with Coronavirus Disease 2019 (COVID-19). During hospitalization, the patient suffered from sudden onset of paraplegia, and urinary retention, and had a T6-T7 sensory level. TM was diagnosed and an extensive workup was performed to rule out other etiologies. Eventually, para-infectious TM associated with COVID-19 was concluded. The patient received pulse methylprednisolone therapy of 1 g/day for 10 consecutive days followed by seven sessions of plasma exchange without a favorable response. The patient then underwent regular physical rehabilitation and tapering oral administration of prednisolone 1 mg/Kg. As a result, weakness in the lower extremities improved slightly after six months. Overall, we suspect a correlation between COVID-19 and TM, however, further studies are required to substantiate the association.

The impacts of anesthetic regimens on the middle cerebral artery occlusion outcomes in male rats.

The middle cerebral artery occlusion (MCAO) model was introduced more than 3 decades ago to simulate human stroke. Till now, it is the most common platform to investigate stroke-induced pathological changes as well as to discover new drugs and treatments. Induction of general anesthesia is mandatory to induce this model, and different laboratories are using various anesthetic drugs, which might affect MCAO results. Therefore, the present study was designed to compare the impacts of several widely used anesthetic regimens on the MCAO outcomes. Here, adult male rats were anesthetized by isoflurane inhalation, intraperitoneal injection of chloral hydrate (CH), intraperitoneal injection of ketamine-xylazine, or subcutaneous administration of ketamine-xylazine, then subjected to 30 min MCAO. Survival rate, body weight change, infarct size, as well as cognitive and neurological performance were evaluated up to 3 days after the surgery. Our findings revealed CH caused the highest, whereas subcutaneous ketamine-xylazine led to the lowest mortality. Meanwhile, there were no significant differences in the body weight loss, infarct size, cognitive impairments, and neurological deficits among the experimental groups. Based on the current results, we proposed that subcutaneous injection of ketamine-xylazine could be an effective anesthetic regimen in the rat model of MCAO with several advantages such as low mortality, cost-effectiveness, safety, ease of administration, and not requiring specialized equipment.

Early and mid-term outcomes of carotid angioplasty and stent placement in 579 patients.

BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) could be considered for preventing stroke in patients with carotid artery stenosis. This study aimed to determine the incidence and the risk factors of the early and mid-term complications associated with CAS. METHODS: This is a retrospective cohort study conducted at Shiraz University of Medical Sciences from March 2011 to March 2019. Patients at high risk and standard risk for carotid endarterectomy were included. The primary composite outcome was defined as stroke, myocardial infarction (MI), and death in the first 30 days after CAS. All-cause mortality, vascular mortality, and stroke were investigated during mid-term follow-up. RESULTS: A total of 579 patients (618 CAS) were recruited (mean age: 71.52 years). Overall, 394 (68.40%), 211 (36.63%), 179 (31.07%), and 96 (16.72%) patients had hypertension, dyslipidemia, diabetes mellitus, or were cigarette smokers, respectively. Primary composite outcomes were observed in 2.59% of patients (1.55% stroke, 0.69% MI, and 1.72% death). Atrial fibrillation was a predictor of primary composite outcome in multivariate logistic regression (p = .048). The presence of total occlusion in the contralateral carotid artery was significantly associated with the risk of stroke in univariate logistic regression (p = .041). The patients were followed for a period ranging from 1 to 83 months. The overall survival rate for all-cause mortality was 93.48% at 1 year, 77.24% at 5 years, and 52.92% at 8 years. All-cause mortality was significantly higher among patients with symptomatic carotid stenosis (p = .014). CONCLUSION: CAS provides acceptable short-term and mid-term outcomes in a unique population of high- and standard-surgical-risk, symptomatic and asymptomatic, octogenarian, and nonoctogenarian patients.

Therapeutic potential of hair follicle-derived stem cell intranasal transplantation in a rat model of ischemic stroke.

BACKGROUND: Stem cell-based therapy has received considerable attention as a potential candidate in the treatment of ischemic stroke; however, employing an appropriate type of stem cells and an effective delivery route are still challenging. In the present study, we investigated the therapeutic effect of safe, noninvasive, and brain-targeted intranasal administration of hair follicle-derived stem cells (HFSCs) in a rat model of ischemic stroke. METHODS: Stem cells were obtained from the adult rat hair follicles. In experiment 1, stroke was induced by 30 min middle cerebral artery occlusion (MCAO) and stem cells were intranasally transplanted immediately after ischemia. In experiment 2, stroke was induced by 120 min MCAO and stem cells were administered 24 h after cerebral ischemia. In all experimental groups, neurological performance, short-term spatial working memory and infarct volume were assessed. Moreover, relative expression of major trophic factors in the striatum and cortex was evaluated by the quantitative PCR technique. The end point of experiment 1 was day 3 and the end point of experiment 2 was day 15. RESULTS: In both experiments, intranasal administration of HFSCs improved functional performance and decreased infarct volume compared to the MCAO rats. Furthermore, NeuN and VEGF expression were higher in the transplanted group and stem cell therapy partially prevented BDNF and neurotrophin-3 over-expression induced by cerebral ischemia. CONCLUSIONS: These findings highlight the curative potential of HFSCs following intranasal transplantation in a rat model of ischemic stroke.

The Hospitalization Rate of Cerebral Venous Sinus Thrombosis before and during COVID-19 Pandemic Era: A Single-Center Retrospective Cohort Study.

OBJECTIVES: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). MATERIALS AND METHODS: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. RESULTS: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P = 0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P = 0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P = 0.015) and malignancy (P = 0.014) in pre-COVID period; and was associated with age (P = 0.025), altered mental status on admission time (P<0.001), malignancy (P = 0.041) and COVID-19 infection (P = 0.008) in COVID-19 period. CONCLUSION: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis before carotid artery stenting: A proof-of-concept, randomized controlled trial.

Background: Remote ischemic preconditioning (RIPC) has been proposed as a possible potential treatment for ischemic stroke. This study aimed to investigate the frequency of micro-embolic brain infarcts after RIPC in patients with stroke who underwent elective carotid artery stenting (CAS) treatment. Methods: This study was managed at Shiraz University of Medical Sciences in southwest Iran. Patients undergoing CAS were randomly allocated into RIPC and control groups. Patients in the RIPC group received three intermittent cycles of 5-minute arm ischemia followed by reperfusion using manual blood cuff inflation/deflation less than 30 minutes before CAS treatment. Afterward, stenting surgery was conducted. Magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC), was acquired within the first 24 hours after CAS. Results: Seventy-four patients were recruited (79.7% men, age: 72.30 ± 8.57). Both groups of RIPC and control had no significant difference in baseline parameters (P > 0.05). Fifteen patients (40.5%) in the RIPC group and 19 (54.1%) patients in the control group developed restricted lesions in DWI MRI. In DWI+ patients, there were no significant differences according to the number of lesions, lesion surface area, largest lesion diameter, cortical infarcts percent, and ipsilateral and bilateral infarcts between the two groups. Conclusion: Although RIPC is a safe and non-invasive modality before CAS to decrease infarcts, this study did not show the advantage of RIPC in the prevention of infarcts following CAS. It may be because of the small sample size.

The neuroprotective properties and therapeutic potential of epidermal neural crest stem cells transplantation in a rat model of vascular dementia.

INTRODUCTION: The incidence rate of senile dementia is rising, and there is no definite cure for it yet. Cell therapy, as a new investigational approach, has shown promising results. Hair bulges with abundant easily accessible neural stem cells permit autologous implantation in irreversible neurodegenerative disorders. METHODS: Fifty rats were randomly divided into 5 groups of control, sham-operation, two-common carotid vessel-occlusion rats that received vehicle (2VO + V), 2VO rats that received 1 × 106 epidermal stem cells (2VO + ESC1), and 2VO rats that received 2.5 × 106 epidermal stem cells (2VO + ESC2) in 300 µl PBS intravenously on days 4, 9, and 14 after surgery. The epidermal neural crest stem cells (EPI-NCSCs) were isolated from hair follicles of rat whiskers. The open-field, passive avoidance, and Morris water maze were used as behavioral tests. The basal-synaptic transmission, long-term potentiation (LTP), and short-term synaptic plasticity were evaluated by field-potential recording of the CA1 hippocampal area. RESULTS: 30 days after the first transplantation in the 2VO + ESC1 group, functional recovery was prominent in anxiety and fear memory compared to the 2VO + ESC2 group, while LTP induction was recovered in both groups of grafted animals without improvement in basal synaptic transmission. These positive recoveries may be related to the release of different neurotrophic factors from grafted cells that can stimulate endogenous neurogenesis and synaptic plasticity. CONCLUSIONS: Our results showed that EPI-NCSCs implantation could rescue LTP and cognitive disability in 2VO rats, while transplantation of 1 million cells showed better performance relative to 2.5 million cells.

The Beneficial Potential of Genetically Modified Stem Cells in the Treatment of Stroke: a Review.

The last two decades have witnessed a surge in investigations proposing stem cells as a promising strategy to treat stroke. Since growth factor release is considered as one of the most important aspects of cell-based therapy, stem cells over-expressing growth factors are hypothesized to yield higher levels of therapeutic efficiency. In pre-clinical studies of the last 15 years that were investigating the efficiency of stem cell therapy for stroke, a variety of stem cell types were genetically modified to over-express various factors. In this review we summarize the current knowledge on the therapeutic efficiency of stem cell-derived growth factors, encompassing techniques employed and time points to evaluate. In addition, we discuss several types of stem cells, including the recently developed model of epidermal neural crest stem cells, and genetically modified stem cells over-expressing specific factors, which could elevate the restorative potential of naive stem cells. The restorative potential is based on enhanced survival/differentiation potential of transplanted cells, apoptosis inhibition, infarct volume reduction, neovascularization or functional improvement. Since the majority of studies have focused on the short-term curative effects of genetically engineered stem cells, we emphasize the need to address their long-term impact.

Aspirin impacts on stem cells: Implications for therapeutic targets.

Despite the regenerative potential of stem cell therapy in pre-clinical investigations, clinical translation of cell-based therapy has not been completely clarified. In recent years, the importance of lifestyle, patient comorbidities, and prescribed medication has attracted more attention in the efficacy of cell therapy. As a nonsteroidal anti-inflammatory drug, aspirin is one of the most prevalent prescribed medications in the clinic for various disorders. Hence, aspirin treatment might affect the efficacy of stem cell therapy. In this regard, the current review focused on the impacts of aspirin on the viability, proliferation, differentiation, and immunomodulatory properties of stem cells in vitro as well as in experimental animal models.

Effect of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) on learning and memory impairment and hippocampal apoptosis induced by intracerebroventricular administration of streptozotocin in rats.

Intracerebroventricular (icv) administration of streptozotocin (STZ) has been used as a metabolic model of sporadic Alzheimer's disease (AD). Erythropoietin (EPO) possesses neuroprotective and memory-improving effects, which might be advantageous in treating different characteristics of AD. Nevertheless, the hematopoietic effect of EPO has hindered its application as a neuroprotective agent. Previous studies have shown that a new Epo derivative called carbamylated Erythropoietin-Fc (CEPO-Fc), yield noticeable neuroprotective effects without affecting hematopoiesis. In this study, the neuroprotective effects of CEPO-Fc on icv-STZ induced memory impairment and hippocampal apoptosis were examined. Adult male Wistar rats weighing 250-300 g were used. STZ was administered on days 1 and 3 (3 mg/kg in divided doses/icv), and CEPO-Fc was administered at the dose of 5000 IU/ip/daily during days 4-14. The animals were trained in Morris water maze during days 15-17, and the memory retention test was performed on the 18th day. Following behavioral studies, the animals were sacrificed and their hippocampi isolated to determine the amounts of cleaved caspase-3 (the landmark of apoptosis). The results showed that CEPO-Fc treatment at the dose of 5000 IU/kg/ip was able to prevent the learning and memory deficit induced by icv-STZ. Western blot analysis revealed that STZ prompted the cleavage of caspase-3 in the hippocampus while pretreatment with CEPO-Fc significantly reduced the cleavage of this protein. Collectively, our findings suggest that CEPO-Fc could restore STZ-induced learning and memory impairment as well as apoptosis in the hippocampal region in a rat model of sporadic AD induced by icv-STZ.

CEPO (carbamylated erythropoietin)-Fc protects hippocampal cells in culture against beta amyloid-induced apoptosis: considering Akt/GSK-3ß and ERK signaling pathways.

The tissue-protective properties of erythropoietin (EPO) have been described in several neurodegenerative diseases models, but erythrocytosis following EPO treatment may lead to deleterious effects. Carbamylated erythropoietin, an EPO derivative lacking hematopoietic side effects, has shown protective properties in some studies. However, it is not known if CEPO protects primary hippocampal cells against Aß25-35 toxicity. The present study aimed to investigate the effect of CEPO-Fc on biochemical alterations in Akt, GSK-3ß, and ERK signaling and cell death induced by Aß25-35 in isolated hippocampal cell culture. The embryonic hippocampal cells were obtained from 18-19 day rat embryos. The cells were exposed with Aß25-35 (20 µM) in the absence or presence of CEPO-Fc (1 or 5 IU) and PI3k and ERK inhibitors. CEPO-Fc at the dose of 5 IU significantly prevented the cell loss and caspase-3 cleavage caused by Aß25-35. Additionally, CEPO-Fc noticeably reversed Aß mediated decrement of Akt and GSK-3ß phosphorylation. With exposure to LY294002, PI3 kinase inhibitor, Akt phosphorylation diminished and CEPO-Fc protective effects disappeared. Furthermore, while CEPO-Fc nullified Aß-induced increment of phospho-ERK, inhibition of ERK activity by PD98059, had no effect on Aß25-35-mediated caspase-3 cleavage and cell toxicity. These results imply that protective effects of CEPO-Fc seem to be mainly exerted through the PI3K/Akt pathway rather than ERK signaling. This study suggested that CEPO-Fc prevents Aß-induced cell toxicity as well as Akt/GSK-3ß and ERK alterations in isolated hippocampal cells. These findings might provide a new perspective on CEPO-Fc protective properties as a prospective remedial factor for neurodegenerative diseases like AD.

Effects of early decompressive craniectomy on functional outcome of patients with malignant middle cerebral artery infarctions.

Background: This study aimed to compare the functional outcome of patients with malignant middle cerebral artery (MCA) infarction who had undergone either early decompressive craniectomy (DC) or optimal medical therapy (OMT). Methods: This study was conducted during a 2-year period in Golestan Hospital of Ahvaz, Iran. The selected patients with malignant MCA infarction who were admitted within 48 hours of presenting signs were included. The patients were randomly assigned to undergo either early DC (n = 12) or OMT (n = 12) in the neurosurgical intensive care unit (ICU). The functional outcomes in the subjects were evaluated with the Glasgow Outcome Scale (GOS) and the National Institutes of Health Stroke Scale (NIHSS) at discharge, 6, and 12-month intervals. Results: The patients who underwent DC had significantly higher GOS at discharge (P = 0.013), 6 (P = 0.022), and 12 (P = 0.042) months as compared to the medical therapy group. However, the NIHSS score did not show any significant difference between the two groups during the study. Likewise, DC was associated with lower mortality at 6 (P = 0.027) and 12 (P = 0.014) months; moreover, the lower mortality rate (P = 0.014), severe disability (P = 0.040), higher good recovery (P < 0.001), and moderate disability (P < 0.001) were observed after 12 months of follow-up. Conclusion: These findings suggest that early DC in patients with malignant MCA can decrease mortality and improve the functional outcome according to GOS criteria compared to medical therapy.

The neuroprotective effect of agmatine against amyloid ß-induced apoptosis in primary cultured hippocampal cells involving ERK, Akt/GSK-3ß, and TNF-α.

ß-Amyloid peptide (Aß), the major element of senile plaques in Alzheimer's disease (AD), has been found to accumulate in brain regions critical for memory and cognition. Deposits of Aß trigger neurotoxic events which lead to neural apoptotic death. The present study examined whether agmatine, an endogenous polyamine formed by the decarboxylation of L-arginine, possesses a neuroprotective effect against Aß-induced toxicity. Primary rat hippocampal cells extracted from the brains of 18-19-day-old embryos were exposed to 10 µM of Aß (25-35) in the absence or presence of agmatine at 150 or 250 µM. Additionally, the involvement of Akt (Protein Kinae B), GSK-3ß (glycogen synthase kinase 3-ß), ERK (Extracellular Signal-Regulated Kinase) and TNF-α (Tumor necrosis factor-α) in the agmatine protection against Aß-induced neurotoxicity was investigated. Agmatine significantly prevented the effect of Aß exposure on cell viability and caspase-3 assays. Furthermore, agmatine considerably restored Aß-induced decline of phospho-Akt and phospho-GSK and blocked Aß-induced increase of phospho-ERK and TNF-alpha. Taken together, these findings might shed light on the protective effect of agmatine as a potential therapeutic agent for AD.

CEPO-Fc (An EPO Derivative) Protects Hippocampus Against Aß-induced Memory Deterioration: A Behavioral and Molecular Study in a Rat Model of Aß Toxicity.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease, characterized by extracellular deposition of senile plaques, mostly amyloid ß-protein (Aß) and neuronal loss. The neuroprotective effects of erythropoietin (EPO) have been reported in some models of neurodegenerative disease, but because of its hematopoietic side effects, its derivatives lacking hematopoietic bioactivity is recommended. In this study, the neuroprotective effects of carbamylated erythropoietin-Fc (CEPO-Fc) against beta amyloid-induced memory deficit were evaluated. Adult male Wistar rats weighing 250-300 g were bilaterally cannulated into CA1. Aß25-35 was administered intrahippocampally for 4 consecutive days (5 µg/2.5 µL/each side/day). CEPO-Fc (500 or 5000 IU) was injected intraperitoneally during days 4-9. Learning and memory performance of rats was assessed on days 10-13 using Morris Water Maze, then hippocampi were isolated and the amount of activated forms of hippocampal MAPKs' subfamily, Akt/GSK-3ß and MMP-2 were analyzed using Western blot. From the behavioral results, it was revealed that CEPO-Fc treatment in both 500 and 5000 IU significantly reversed Aß-induced learning and memory deterioration. From the molecular analysis, an increment of MAPKs and MMP-2 activity and an imbalance in Akt/GSK-3ß signaling after Aß25-35 administration was observed. CEPO-Fc treatment prevented the elevation of hippocampal of P38, ERK, MMP-2 activity and also Akt/GSK-3ß signaling impairment induced by Aß25-35 but it had no effect on JNK. It seems that CEPO-Fc prevents Aß-induced learning and memory deterioration, and also modulates hippocampal MAPKs, Akt/GSK-3ß and MMP-2 activity. This study suggests that CEPO-Fc can be considered as a potential therapeutic strategy for memory deficits like AD.