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Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 43924

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Special Issue Editors

Prof. Dr. Antoni Camins Espuny

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Guest Editor

1. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
2. Institut de Neurociències, University of Barcelona, 08028 Barcelona, Spain
3. Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Juan Carlos III, 28031 Madrid, Spain
Interests: Alzheimer's disease; aging; apoptosis; neuropharmacology; epilepsy
Special Issues, Collections and Topics in MDPI journals

Dr. Miren Ettcheto

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Guest Editor

1. Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
2. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
3. Institute of Neurosciences, University of Barcelona, Barcelona, Spain
Interests: neuropharmacology; neuroptotection; cognition; Alzheimer’s disease; Parkinson's disease

Special Issue Information

Dear Colleagues,

The increasing prevalence of epilepsy and neurodegenerative disorders is a matter of global concern. Whereas epilepsy is a severe brain disorder that affects around 50 million people worldwide, neurodegenerative diseases such as Parkinson’s disease (PD) and especially Alzheimer’s disease (AD) are increasing in parallel to the aging of the population in developed countries. Although current treatments with antiepileptic drugs can be effective in the control of the symptoms, one of the major problems in epilepsy treatment is the loss of drug response. The precise causes of this phenomenon, known as “refractory epilepsy”, remain to be elucidated, although a number of studies are working on this area. On another front, the currently available treatments for neurodegenerative diseases are only palliative. Therefore, the study of new synthetic and natural products, as well as alternative strategies, is of paramount importance to find a cure to these disorders.

Prof. Dr. Antoni Camins Espuny
Dr. Miren Ettcheto
Guest Editors

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Keywords

Epilepsy
Alzheimer’s
Parkinson’s
Neurological disorders

Published Papers (11 papers)

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Research

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23 pages, 5545 KiB

Open AccessArticle

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

by Vasily A. Aleshin, Anastasia V. Graf, Artem V. Artiukhov, Alexandra I. Boyko, Alexander L. Ksenofontov, Maria V. Maslova, Isabel Nogués, Martino L. di Salvo and Victoria I. Bunik

Pharmaceuticals 2021, 14(8), 737; https://doi.org/10.3390/ph14080737 - 28 Jul 2021

Cited by 10 | Viewed by 2959

Abstract

The disturbed metabolism of vitamins B1 or B6, which are essential for neurotransmitters homeostasis, may cause seizures. Our study aims at revealing therapeutic potential of vitamins B1 and B6 by estimating the short- and long-term effects of their combined administration with the seizure inductor pentylenetetrazole (PTZ). The PTZ dose dependence of a seizure and its parameters according to modified Racine’s scale, along with delayed physiological and biochemical consequences the next day after the seizure are assessed regarding sexual dimorphism in epilepsy. PTZ sensitivity is stronger in the female than the male rats. The next day after a seizure, sex differences in behavior and brain biochemistry arise. The induced sex differences in anxiety and locomotor activity correspond to the disappearance of sex differences in the brain aspartate and alanine, with appearance of those in glutamate and glutamine. PTZ decreases the brain malate dehydrogenase activity and urea in the males and the phenylalanine in the females. The administration of vitamins B1 and B6 24 h before PTZ delays a seizure in female rats only. This desensitization is not observed at short intervals (0.5–2 h) between the administration of the vitamins and PTZ. With the increasing interval, the pyridoxal kinase (PLK) activity in the female brain decreases, suggesting that the PLK downregulation by vitamins contributes to the desensitization. The delayed effects of vitamins and/or PTZ are mostly sex-specific and interacting. Our findings on the sex differences in sensitivity to epileptogenic factors, action of vitamins B1/B6 and associated biochemical events have medical implications. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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11 pages, 2017 KiB

Open AccessArticle

Transcranial Focal Electrical Stimulation Modifies Biogenic Amines’ Alterations Induced by 6-Hydroxydopamine in Rat Brain

by Cesar Emmanuel Santana-Gómez, Daniel Pérez-Pérez, Daniel Fonseca-Barriendos, Oscar Arias-Carrión, Walter Besio and Luisa Rocha

Pharmaceuticals 2021, 14(8), 706; https://doi.org/10.3390/ph14080706 - 21 Jul 2021

Cited by 1 | Viewed by 2451

Abstract

Transcranial focal stimulation (TFS) is a non-invasive neuromodulation strategy with neuroprotective effects. On the other hand, 6-hidroxidopamine (6-OHDA) induces neurodegeneration of the nigrostriatal system producing modifications in the dopaminergic, serotoninergic, and histaminergic systems. The present study was conducted to test whether repetitive application of TFS avoids the biogenic amines’ changes induced by the intrastriatal injection of 6-OHDA. Experiments were designed to determine the tissue content of dopamine, serotonin, and histamine in the brain of animals injected with 6-OHDA and then receiving daily TFS for 21 days. Tissue content of biogenic amines was evaluated in the cerebral cortex, hippocampus, amygdala, and striatum, ipsi- and contralateral to the side of 6-OHDA injection. Results obtained were compared to animals with 6-OHDA, TFS alone, and a Sham group. The present study revealed that TFS did not avoid the changes in the tissue content of dopamine in striatum. However, TFS was able to avoid several of the changes induced by 6-OHDA in the tissue content of dopamine, serotonin, and histamine in the different brain areas evaluated. Interestingly, TFS alone did not induce significant changes in the different brain areas evaluated. The present study showed that repetitive TFS avoids the biogenic amines’ changes induced by 6-OHDA. TFS can represent a new therapeutic strategy to avoid the neurotoxicity induced by 6-OHDA. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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19 pages, 10247 KiB

Open AccessArticle

Celecoxib Decrease Seizures Susceptibility in a Rat Model of Inflammation by Inhibiting HMGB1 Translocation

by Hadeel Alsaegh, Hala Eweis, Fatemah Kamel and Aziza Alrafiah

Pharmaceuticals 2021, 14(4), 380; https://doi.org/10.3390/ph14040380 - 19 Apr 2021

Cited by 11 | Viewed by 2921

Abstract

The risk of developing epilepsy is strongly linked to peripheral inflammatory disorders in humans. High-mobility group box protein 1 (HMGB1) has the most focus for being a suspect in this scenario. The current study aimed to detect the celecoxib effect, an anti-inflammatory drug, on decreasing seizure susceptibility and organ damage in lipopolysaccharides (LPS)/pilocarpine (PILO) pretreated Wistar rats. Rats were divided into 6 groups (8 each): group 1 (control), group 2 (PILO), group 3 (PILO+LPS), group 4 (PILO+LPS+(VPA) Valproic acid), group 5 (PILO+LPS+Celecoxib), and group 6 (PILO+LPS+VPA+Celecoxib). LPS was used to induce sepsis and PILO to induce seizures. Oxidative stress markers, pro-inflammatory cytokines, and HMGB1 levels in serum and brain homogenate were evaluated. Histopathological studies were conducted on the hippocampus, liver, lung, and kidney. Treatment with celecoxib either alone or in combination with VPA significantly reduced Racine score and delays latency to generalized tonic-clonic seizures onset with a significant decrease in hippocampal levels of pro-inflammatory cytokines, oxidative stress markers, and increase in reduced glutathione. In addition, celecoxib treatment either alone or in combination with VPA suppressed HMGB1translocation into peripheral circulation more than treatment with VPA alone. Furthermore, hippocampus, liver, lung, and kidney histopathological changes were improved in contrast to other epileptic groups. Celecoxib either alone or combined with VPA has antiepileptic and multiorgan protective effects on acute seizures and inflammatory models induced by PILO with LPS. It decreased histopathological findings, oxidative, and inflammatory effects induced by VPA and LPS. This might be due to its anti-oxidative, anti-inflammatory and anti-HMGB1 mediated effects. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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13 pages, 2137 KiB

Open AccessArticle

Adenosine A1 Receptor Agonist (R-PIA) before Pilocarpine Modulates Pro- and Anti-Apoptotic Factors in an Animal Model of Epilepsy

by Daniele Suzete Persike, Rebeca Padrão Amorim Puccinelli and Maria José da Silva Fernandes

Pharmaceuticals 2021, 14(4), 376; https://doi.org/10.3390/ph14040376 - 18 Apr 2021

Cited by 1 | Viewed by 1996

Abstract

We aimed to characterize the mechanisms involved in neuroprotection by R-PIA administered before pilocarpine-induced seizures. Caspase-1 and caspase-3 activities were assayed using fluorimetry, and cathepsin D, HSP-70, and AKT expression levels were assayed using Western Blot of hippocampal samples. R-PIA was injected before pilocarpine (PILO), and four groups were studied at 1 h 30 min and 7 days following initiation of status epilepticus (SE): PILO, R-PIA+PILO, SALINE, and R-PIA+SALINE. At 1 h 30 min, significantly higher activities of caspase-1 and -3 were observed in the PILO group than in the SALINE group. Caspase-1 and -3 activities were higher in the R-PIA+PILO group than in the PILO group. At 7 days following SE, caspase-1 and -3 activities were higher than in the initial post-seizure phase compared to the SALINE group. The pretreatment of rats receiving PILO significantly reduced caspase activities compared to the PILO group. Expression of HSP-70, AKT, and cathepsin D was significantly higher in the PILO group than in the SALINE. In the R-PIA+PILO group, the expression of AKT and HSP-70 was greater than in rats receiving only PILO, while cathepsin D presented decreased expression. Pretreatment with R-PIA in PILO-injected rats strongly inhibited caspase-1 and caspase-3 activities and cathepsin D expression. It also increased expression levels of the neuroprotective proteins HSP-70 and AKT, suggesting an important role in modulating the cellular survival cascade. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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12 pages, 6791 KiB

Open AccessArticle

Cannabidiol (CBD) Alters the Functionality of Neutrophils (PMN). Implications in the Refractory Epilepsy Treatment

by Claudia Taborda Gómez, Fabiana Lairion, Marisa Repetto, Miren Ettcheto, Amalia Merelli, Alberto Lazarowski and Jerónimo Auzmendi

Pharmaceuticals 2021, 14(3), 220; https://doi.org/10.3390/ph14030220 - 05 Mar 2021

Cited by 6 | Viewed by 3084

Abstract

Cannabidiol (CBD), a lipophilic cannabinoid compound without psychoactive effects, has emerged as adjuvant of anti-epileptic drugs (AEDs) in the treatment of refractory epilepsy (RE), decreasing the severity and/or frequency of seizures. CBD is considered a multitarget drug that could act throughout the canonical endocannabinoid receptors (CB1-CB2) or multiple non-canonical pathways. Despite the fact that the CBD mechanism in RE is still unknown, experiments carried out in our laboratory showed that CBD has an inhibitory role on P-glycoprotein excretory function, highly related to RE. Since CB2 is expressed mainly in the immune cells, we hypothesized that CBD treatment could alter the activity of polymorphonuclear neutrophils (PMNs) in a similar way that it does with microglia/macrophages and others circulating leukocytes. In vitro, CBD induced PMN cytoplasmatic vacuolization and proapoptotic nuclear condensation, associated with a significantly decreased viability in a concentration-dependent manner, while low CBD concentration decreased PMN viability in a time-dependent manner. At a functional level, CBD reduced the chemotaxis and oxygen consumption of PMNs related with superoxide anion production, while the singlet oxygen level was increased suggesting oxidative stress damage. These results are in line with the well-known CBD anti-inflammatory effect and support a potential immunosuppressor role on PMNs that could promote an eventual defenseless state during chronic treatment with CBD in RE. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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26 pages, 7174 KiB

Open AccessArticle

Zingerone Targets Status Epilepticus by Blocking Hippocampal Neurodegeneration via Regulation of Redox Imbalance, Inflammation and Apoptosis

by Summya Rashid, Adil Farooq Wali, Shahzada Mudasir Rashid, Rana M. Alsaffar, Ajaz Ahmad, Basit L. Jan, Bilal Ahmad Paray, Saeed M. A. Alqahtani, Azher Arafah and Muneeb U. Rehman

Pharmaceuticals 2021, 14(2), 146; https://doi.org/10.3390/ph14020146 - 11 Feb 2021

Cited by 17 | Viewed by 2958

Abstract

Epilepsy is an intricate neurological disease where the neurons are severely affected, leading to the mortality of millions worldwide. Status epilepticus (SE), induced by lithium chloride (LiCl) and pilocarpine, is the most accepted model for epilepsy. The current work aims to unravel the mechanisms underlying the anti-epileptic efficacy of zingerone (an active ingredient of ginger), which has beneficial pharmacological activities on seizure-induced behavioral, histological, neurochemical, and molecular patterns in mice. Zingerone restored cognitive function by diminishing seizure activity, escape latency, and subsequent hippocampal damage manifested in histology. Seizures are associated with local inflammation, redox imbalance, and neural loss, confirmed by the present study of SE, and was attenuated by zingerone treatment. Nuclear factor-kappa B and its downstream signaling molecules (TNF-α, IL-1β, IL-6, NO, MPO) were activated in the LiCl-and-pilocarpine-induced group leading to inflammatory signaling, which was substantially ameliorated by zingerone treatment. The intrinsic apoptotic process was triggered subsequent to SE, as demonstrated by augmentation of cleaved caspase-3, downregulation of Bcl-2. However, zingerone treatment downregulated caspase-3 and upregulated Bcl-2, increasing cell survival and decreasing hippocampal neural death, deciphering involvement of apoptosis in SE. Therefore, zingerone plays an essential role in neuroprotection, probably by precluding oxidative stress, inflammation, and obstructing the mitochondrial pathway of apoptosis. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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17 pages, 1867 KiB

Open AccessArticle

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

by Anna-Maria Costa, Chiara Lucchi, Asiye Malkoç, Cecilia Rustichelli and Giuseppe Biagini

Pharmaceuticals 2021, 14(2), 127; https://doi.org/10.3390/ph14020127 - 06 Feb 2021

Cited by 19 | Viewed by 2804

Abstract

Abrupt withdrawal from antiepileptic drugs is followed by increased occurrence of epileptic seizures, a phenomenon known as the “rebound effect”. By stopping treatment with levetiracetam (LEV 300 mg/kg/day, n = 15; vs. saline, n = 15), we investigated the rebound effect in adult male Sprague-Dawley rats. LEV was continuously administered using osmotic minipumps, 7 weeks after the intraperitoneal administration of kainic acid (15 mg/kg). The effects of LEV were determined by comparing time intervals, treatments, and interactions between these main factors. Seizures were evaluated by video-electrocorticographic recordings and power band spectrum analysis. Furthermore, we assessed endogenous neurosteroid levels by liquid chromatography-electrospray-tandem mass spectrometry. LEV significantly reduced the percentage of rats experiencing seizures, reduced the seizure duration, and altered cerebral levels of neurosteroids. In the first week of LEV discontinuation, seizures increased abruptly up to 700% (p = 0.002, Tukey’s test). The power of delta band in the seizure postictal component was related to the seizure occurrence after LEV withdrawal (r² = 0.73, p < 0.001). Notably, allopregnanolone hippocampal levels were positively related to the seizure occurrence (r² = 0.51, p = 0.02) and to the power of delta band (r² = 0.67, p = 0.004). These findings suggest a role for the seizure postictal component in the rebound effect, which involves an imbalance of hippocampal neurosteroid levels. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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25 pages, 7986 KiB

Open AccessArticle

Anakinra Reduces Epileptogenesis, Provides Neuroprotection, and Attenuates Behavioral Impairments in Rats in the Lithium–Pilocarpine Model of Epilepsy

by Alexandra V. Dyomina, Olga E. Zubareva, Ilya V. Smolensky, Dmitry S. Vasilev, Maria V. Zakharova, Anna A. Kovalenko, Alexander P. Schwarz, Alexander M. Ischenko and Aleksey V. Zaitsev

Pharmaceuticals 2020, 13(11), 340; https://doi.org/10.3390/ph13110340 - 25 Oct 2020

Cited by 22 | Viewed by 3576

Abstract

Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1β (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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Review

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23 pages, 5080 KiB

Open AccessReview

Epilepsy in Neurodegenerative Diseases: Related Drugs and Molecular Pathways

by Amanda Cano, Elena Fonseca, Miren Ettcheto, Elena Sánchez-López, Itziar de Rojas, Silvia Alonso-Lana, Xavier Morató, Eliana B. Souto, Manuel Toledo, Mercè Boada, Marta Marquié and Agustín Ruíz

Pharmaceuticals 2021, 14(10), 1057; https://doi.org/10.3390/ph14101057 - 18 Oct 2021

Cited by 26 | Viewed by 9016

Abstract

Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca²⁺ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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23 pages, 1749 KiB

Open AccessReview

The Cross Talk between Underlying Mechanisms of Multiple Sclerosis and Epilepsy May Provide New Insights for More Efficient Therapies

by Atefeh Rayatpour, Sahar Farhangi, Ester Verdaguer, Jordi Olloquequi, Jesus Ureña, Carme Auladell and Mohammad Javan

Pharmaceuticals 2021, 14(10), 1031; https://doi.org/10.3390/ph14101031 - 11 Oct 2021

Cited by 6 | Viewed by 3588

Abstract

Despite the significant differences in pathological background of neurodegenerative diseases, epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer’s disease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shown that the risk of developing epilepsy is three to six times higher in patients with MS compared to the general population. In this context, understanding the pathological processes underlying this connection will allow for the targeting of the common and shared pathological pathways involved in both conditions, which may provide a new avenue in the management of neurological disorders. This review provides an outlook of what is known so far about the bidirectional association between epilepsy and MS. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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22 pages, 749 KiB

Open AccessReview

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

by Saghar Rabiei Poor, Miren Ettcheto, Amanda Cano, Elena Sanchez-Lopez, Patricia Regina Manzine, Jordi Olloquequi, Antoni Camins and Mohammad Javan

Pharmaceuticals 2021, 14(9), 890; https://doi.org/10.3390/ph14090890 - 01 Sep 2021

Cited by 20 | Viewed by 7073

Abstract

Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications 2021)

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