Evaluation of hippocampal arylalkylamine N-acetyltransferase activity in amyloid-ß neurotoxicity.

Arylalkylamine N-acetyltransferase (AANAT), a rate-limiting enzyme in melatonin synthesis, is present in extra-pineal tissues such as the hippocampus. The hippocampal AANAT activity in amyloid ß (Aß) neurotoxicity has not been exactly defined. Adult male rats received bilateral intra-CA1 Aß administration. The hippocampus tissue sampling was performed 2, 12, and 24 h after Aß injection in the morning and night. The inflammation was monitored using tumor necrosis factor-alpha (TNF-α) immunohistochemistry. The AANAT enzyme activity and melatonin levels were measured using western blotting and high-performance liquid chromatography. The sampling in the morning vs night showed no significant differences in the AANAT activity. The Aß increased the area of TNF-α positive staining 24 h after injection, which indicated the induction of an inflammatory context. It was accompanied by a significant reduction in AANAT activity and hippocampal melatonin. A reverse correlation was also detected between TNF-α and AANAT activity in the 24-h group. The TNF-α positive area was significantly increased in the 24-h group as compared to the 12-h group. Data showed that inflammatory processes began 12 h after the Aß injection and augmented 24 h later. In the second experiment, the impact of Aß injection on hippocampus AANAT activity was examined in the pinealectomized (PIN×) animals. The PIN× per se did not affect the hippocampal AANAT and melatonin levels. However, there was a significant decrease in hippocampal melatonin in the PIN×+Aß group. The findings suggest the accompanying hippocampal inflammatory context and AANAT enzyme activity reduction in early stages after Aß administration. Understanding the underlying mechanism of the decreased AANAT activity may suggest new treatment strategies.

The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme.

In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.

Recent advances in glioblastoma multiforme therapy: A focus on autophagy regulation.

Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.

Advantages and drawbacks of dexamethasone in glioblastoma multiforme.

The most widespread, malignant, and deadliest type of glial tumor is glioblastoma multiforme (GBM). Despite radiation, chemotherapy, and radical surgery, the median survival of afflicted individuals is about 12 months. Unfortunately, existing therapeutic interventions are abysmal. Dexamethasone (Dex), a synthetic glucocorticoid, has been used for many years to treat brain edema and inflammation caused by GBM. Several investigations have recently shown that Dex also exerts antitumoral effects against GBM. On the other hand, more recent disputed findings have questioned the long-held dogma of Dex treatment for GBM. Unfortunately, steroids are associated with various undesirable side effects, including severe immunosuppression and metabolic changes like hyperglycemia, which may impair the survival of GBM patients. Current ideas and concerns about Dex's effects on GBM cerebral edema, cell proliferation, migration, and its clinical outcomes were investigated in this study.

How do phosphodiesterase-5 inhibitors affect cancer? A focus on glioblastoma multiforme.

Since the discovery of phosphodiesterase-5 (PDE5) enzyme overexpression in the central nervous system (CNS) malignancies, investigations have explored the potential capacity of current PDE5 inhibitor drugs for repositioning in the treatment of brain tumors, notably glioblastoma multiforme (GBM). It has now been recognized that these drugs increase brain tumors permeability and enhance standard chemotherapeutics effectiveness. More importantly, studies have highlighted the promising antitumor functions of PDE5 inhibitors, e.g., triggering apoptosis, suppressing tumor cell growth and invasion, and reversing tumor microenvironment (TME) immunosuppression in the brain. However, contradictory reports have suggested a pro-oncogenic role for neuronal cyclic guanosine monophosphate (cGMP), indicating the beneficial function of PDE5 in the brain of GBM patients. Unfortunately, due to the inconsistent preclinical findings, only a few clinical trials are evaluating the therapeutic value of PDE5 inhibitors in GBM treatment. Accordingly, additional studies should be conducted to shed light on the precise effect of PDE5 inhibitors in GBM biology regarding the existing molecular heterogeneities among individuals. Here, we highlighted and discussed the previously investigated mechanisms underlying the impacts of PDE5 inhibitors in cancers, focusing on GBM to provide an overview of current knowledge necessary for future studies.

Mechanistic insight into the role of metformin in Alzheimer's disease.

Alzheimer's disease (AD), a type of dementia, is characterized by progressive memory decline and cognition impairment. Despite the considerable body of evidence regarding AD pathophysiology, current therapies merely slow down the disease progression, and a comprehensive therapeutic approach is unavailable. Accordingly, finding an efficient multifunctional remedy is necessary to blunt the increasing rate of AD incidence in the upcoming years. AD shares pathophysiological similarities (e.g., impairment of cognitive functions, insulin sensitivity, and brain glucose metabolism) with noninsulin-dependent diabetes mellitus (NIDDM), which offers the utilization of metformin, a biguanide hypoglycemic agent, as an alternative therapeutic approach in AD therapy. Emerging evidence has revealed the impact of metformin in patients suffering from AD. It has been described that metformin employs multiple mechanisms to improve cognition and memory impairment in pre-clinical AD models, including reduction of hippocampal amyloid-beta (Aß) plaque and neurofibrillary tangles (NFTs) load, suppression of inflammation, amelioration of mitochondrial dysfunction and oxidative stress, restriction of apoptotic neuronal death, and induction of neurogenesis. This review discusses the pre-clinical evidence, which may shed light on the role of metformin in AD and provide a more comprehensive mechanistic insight for future studies in this area of research.

The Ameliorative Impact of Centella asiatica on the Working Memory Deficit in Streptozotocin-induced Rat Model of Alzheimer Disease.

Introduction: Alzheimer disease (AD) is a complex neurodegenerative disorder with a progressive nature leading to neural damage and cognitive and memory deficit. The present study investigated the neuroprotective effects of Centella asiatica (CA) in Streptozotocin (STZ)-induced rat model of memory impairment and neuronal damage. Methods: The intracerebroventricular infusion of STZ (3 mg/rat) or saline (as the vehicle) was performed on days 1 and 3. CA (150 and 300 mg/kg/d) was administered through oral gavage for 21 days after model induction. We used the Y-maze test to assess the working memory-related performances of animals. Rats were then sacrificed, and their hippocampi were harvested for evaluation of neuronal density in the cornu ammonis (CA1, CA2, CA3) and Dentate Gyrus (DG) regions using stereology technique. Results: The intracerebroventricular infusion of STZ caused significant working memory impairment demonstrated in the Y-maze apparatus, with a significant decrease in alternative behavior compared to control animals (40.67±2.04 vs 73.00±1.88, P<0.0001). Oral administration of CA (150 and 300 mg/kg each day) for 21 days significantly improved STZ-induced working memory deficit (55.33±3.34 and 57.17±3.81 vs 40.67±2.04, P<0.013, P<0.004, respectively). Furthermore, 21 days of consecutive administration of CA significantly ameliorated STZ-induced neuronal loss in the CA1, CA2, and DG subfields of the hippocampus. Conclusion: Overall, these data demonstrate that CA increases neuronal density and improves cognitive impairment in the STZ-induced rat model of AD, thereby having promising therapeutic potential for neurodegenerative disorders. Accordingly, further studies are needed to determine the exact molecular mechanism of CA protective effects in brain disorders, particularly AD. Highlights: Centella asiatica (CA) improved the STZ-induced working memory deficit.CA could prevent hippocampal neural cell loss dose-dependent manner.CA improved memory through mitigating neuronal loss in hippocampus. Plain Language Summary: Memory loss is the first signs of dementia. It is well known that a healthy diet might be as good for your brain as it is for your heart. Numerous traditionally used medicinal herbs could significantly affect key events culminating in dementia and Alzheimer's disease. Centella asiatica, commonly known as Gotu Kola or Indian Pennywort, is a tropical, medicinal plant native to Southeast Asian countries. It is one of the becoming popular medicinal plants in the world. Centella asiatica (CA) is widely used in different traditional medicine systems for various purposes, such as reducing blood pressure, memory enhancement, and promoting longevity. In the present study, we tested the possible impact of CA leaf and stem extract in an animal model of memory damage. Memory impairment was induced in adult rats by intracerebral infusion of a neurotoxin chemical. Then, the memory-impaired animals were orally treated with 150-300 mg/kg of CA extract for 21 days. Finally, we tested their working memory by placing them in a Y-maze apparatus. Furthermore, their most involved brain part (hippocampus) was dissected, and its cell density was evaluated. Our findings exhibited that CA treatment considerably improved rats' memory performance, indicating by enhancing working memory score in the Y-maze task. In addition, CA treatment significantly prevented neuronal cell loss in the hippocampus of memory-impaired rats. This study shows that CA has beneficial effects on memory and cognitive function.

Effect of histone acetylation on maintenance and reinstatement of morphine-induced conditioned place preference and ΔFosB expression in the nucleus accumbens and prefrontal cortex of male rats.

Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ΔFosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5 mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1 mg/kg) was administered to induce reinstatement. H4 acetylation and ΔFosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25 mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20 mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ΔFosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.

PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) ameliorate learning and memory deficit in a rat model of Alzheimer's disease: Potential participation of STIMs.

The amyloid-beta (Aß) fibrillation process seems to execute a principal role in the neuropathology of Alzheimer's disease (AD). Accordingly, novel therapeutic plans have concentrated on the inhibition or degradation of Aß oligomers and fibrils. Biocompatible nanoparticles (NPs), e.g., gold and iron oxide NPs, take a unique capacity in redirecting Aß fibrillation kinetics; nevertheless, their impacts on AD-related memory impairment have not been adequately evaluated in vivo. Here, we examined the effect of commercial PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) on the learning and memory of an AD-animal model. The outcomes demonstrated the dose-dependent effect of SPIONs on Aß fibrillation and learning and memory processes. In vitro and in vivo findings revealed that Low doses of SPIONs inhibited Aß aggregation and ameliorated learning and memory deficit in the AD model, respectively. Enhanced level of hippocampal proteins, including brain-derived neurotrophic factor, BDNF, phosphorylated-cAMP response element-binding protein, p-CREB, and stromal interaction molecules, e.g., STIM1 and STIM2, were also observed. However, at high doses, SPIONs did not improve the detrimental impacts of Aß fibrillation on spatial memory and hippocampal proteins expression. Overall, we revealed the potential capacity of SPIONs on retrieval of behavioral and molecular manifestations of AD in vivo, which needs further investigations to determine the mechanistic effect of SPIONs in the AD conundrum.

Anxiolytic impact of Apelin-13 in a rat model of Alzheimer's disease: Involvement of glucocorticoid receptor and FKBP5.

Apelin-13 is known to be one of the predominant neuropeptides with marked protective role in circuits involved in mood disturbances. The most putative hypothesis in pathophysiology of Alzheimer's disease (AD) is Amyloid beta (Aß) aggregation which interrupt proper function of hypothalamic-pituitary-adrenal (HPA) axis and are associated with anxiety. Here, we assessed the potential anxiolytic effect of Apelin-13 in a rodent cognitive impairment model induced by intrahippocampal Aß 25-35 administration. We evaluated the memory impairment and anxiogenic behavior using shuttle box and Elevated plus maze apparatuses. We also measured the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP5) expression as important markers showing the proper feedback mechanism within the HPA axis. Our findings showed that Aß 25-35 administration induced memory impairment and anxiety behaviors. Apelin-13 exerted the anxiolytic effects and provided protection against Aß 25-35 -induced passive avoidance memory impairment. Moreover, Apelin-13 caused an increase in GR and a decrease in FKBP5 expression levels in Aß 25-35 treated animals. Taken together, these findings showed the anxiolytic effect of Apelin-13. This effect at least in part, may be mediated through the regulation of GR and FKBP5 expression levels which have a pivotal role in the appropriate negative feedback mechanism within the HPA axis. These data suggest that Apelin-13 might be considered as a potential neuropeptide defense that reduces anxiety along with neuroprotective effect against the Aß 25-35 -induced injury.

Impact of Gold Nanoparticles on Amyloid ß-Induced Alzheimer's Disease in a Rat Animal Model: Involvement of STIM Proteins.

Alzheimer's disease (AD) is the most common type of neurodegenerative amyloid disorder causing progressive cognitive decline and memory loss. A considerable number of therapies for AD rely on inhibition/delay/dissociation of amyloid beta (Aß) oligomers and fibrils. In this case, nanoparticles (NPs) demonstrated substantial effects on the Aß fibrillation process; however, their effects on progressive cognitive decline and memory have been poorly investigated in vivo. In this study, acquisition and retention of spatial learning and memory are studied in a rat animal model of AD after intrahippocampal (IH) and intraperitoneal (IP) injections of a model NP, i.e., gold NPs (AuNPs). The outcomes revealed that the AuNPs could improve the acquisition and retention of spatial learning and memory in Aß treated rats as indicated by decreased time (Aß: 39.60 ± 3.23 s vs Aß+AuNPs: 25.78 ± 2.80 s) and distance (Aß: 917.98 ± 50.81 cm vs Aß+AuNPs: 589.09 ± 65.96 cm) of finding the hidden platform during training days and by increased time spent in the target quadrant (Aß: 19.40 ± 0.98 s vs Aß+AuNPs: 29.36 ± 1.14 s) in the probe test in Morris water maze (MWM). Expression of brain-derived neurotrophic factor, BDNF, cAMP response element binding protein, CREB, and stromal interaction molecules, e.g., STIM1 and STIM2 was also increased, supporting improved neural survival. Our outcomes may pave a way for mechanistic insights toward the role of NPs on retrieval of the deteriorated behavioral functions in brain tissue after AD outbreak.

Protective role of Apelin-13 on amyloid ß25-35-induced memory deficit; Involvement of autophagy and apoptosis process.

Alzheimer's disease (AD) by progressive neurodegenerative pattern is associated with autophagy stress which is suggested as a potential cause of amyloid ß (Aß) aggregation and neural loss. Apelin-13, a neuropeptide with modulatory effect on autophagy, has been shown the beneficial effects on neural cell injuries. We investigated the effect of Apelin-13 on Aß-induced memory deficit as well as autophagy and apoptosis processes. We performed bilateral intra-CA1 injection of Aß25-35 alone or in combination with Apelin-13. Spatial reference and working memory was evaluated using the Morris water maze (MWM) and Y-maze tests. Hippocampus was harvested on 2, 5, 10 and 21 days after Aß injection. The light chain 3 (LC3II/I) ratio, histone deacetylase 6 (HDAC6) level, Caspase-3 cleavage, and mTOR phosphorylation were assessed using western blot technique. Intra-CA1 injection of Aß caused impairment of working and spatial memory. We observed higher LC3II/I ratio, cleaved caspase-3 and lower HDAC6, and p-mTOR/mTOR ratio in Aß-treated animals. Apelin-13 provided significant protection against the destructive effects of Aß on working and spatial memory. Apelin-13 prevented the increase of LC3II/I ratio and cleaved caspase-3 on days 10 and 21 after injection of Aß. It also limited the Aß-induced reduction in HDAC6 expression. This implies that Apelin-13 has suppressed both autophagy and apoptosis. Our findings suggested that the neuroprotection of Apelin-13 may be in part related to autophagy and apoptosis inhibition via the mTOR signaling pathway. Apelin-13 may be a promising approach to improve memory impairment and potentially pave the way for new therapeutic plans in AD.