46 research outputs found

    JNK isoforms control adult mammal hippocampal neurogenesis

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    [eng] In mammals, the term "Adult Neurogenesis” (AN) defines the process through which, throughout adulthood, new neurons are produced from neural stem cells (NSC). These NSC are located in a specific niche, concretely, in the subventricular zone (SVZ), lining the lateral ventricles, and in the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Controversially, new data have questioned the existence of this AN in the human brain seeing how only populations of immature neurons (IN), broadly dispersed within SGZ, have been detected. Either way, neurogenic activity in the hippocampus has been correlated with learning, memory formation and behavioral responses to stress, just like with the pathophysiology of many brain diseases and mood disorders. Various extracellular and intracellular stimuli have been shown to modulate survival, proliferation, and differentiation of adult-born cells in the hippocampus, especially through conserved stimuli-response mechanisms like the JNKs. In the present review, the JNK pathway and their control of adult hippocampal neurogenesis are described, evidencing the critical role of isoform JNK1.[cat] En mamíferos, el término “Neurogenesis Adulta (NA)”, se define como el proceso a través del cual, en adultos, se producen nuevas neuronas granulares a partir de células madre neurales (CMN). Estas CMN estan ubicadas en microambientes específicos, en concreto en la zona subventicular (ZSV), recubriendo los ventriculos laterales, y en la zona subgranular (ZSG) del giro dentado del hipocampo (GD). Sin embargo, nuevas informaciones han cuestionado la existencia de este proceso de neurogenesis adulta en el cerebro humano, ya que solamente se han detectado poblaciones de neuronas inmaduras (NI) dispersas a lo largo de la ZSG. Independientemente, la existencia de una actividad neurogénica en el hipocampo adulto se ha correlacionado con el aprendizaje, la formación de memoria y en el comportamiento ante situaciones de estrés, así como en la patofisiologia de diferentes patologías del cerebro, incluso en casos de alteraciones del estado de ánimo. Se ha demostrado que diferentes estímulos extracelulares e intracelulares controlan la supervivencia, la proliferación y la diferenciación de las nuevas neuronas del hipocampo, especialmente a través de mecanismos conservados de respuesta a estímulos como las JNKs. En la presente revisión se describe las JNK y su control de la neurogénesis hipocampal adulta, evidenciando el papel crucial de la isoforma JNK1

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

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    Despite the significant differences in pathological background of neurodegenerative diseases,epileptic seizures are a comorbidity in many disorders such as Huntington disease (HD), Alzheimer 'sdisease (AD), and multiple sclerosis (MS). Regarding the last one, specifically, it has been shownthat the risk of developing epilepsy is three to six times higher in patients with MS compared tothe general population. In this context, understanding the pathological processes underlying thisconnection will allow for the targeting of the common and shared pathological pathways involvedin 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 betweenepilepsy and M

    Role of JNK in neurodegenerative diseases

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    Podeu consultar el llibre complet a: http://hdl.handle.net/2445/32393The c-Jun N-terminal kinases (JNK) are members of the MAPK family and can be activated by different stimuli such as cellular stress, heat shock and ultra-violet irradiation. JNKs have different physiological functions and they have been linked to apoptosis in different cell types. Therefore, the JNK signalling pathway is an important target to prevent cell death. In the present chapter, the role of JNKs in neurodegenerative diseases will be discussed, as well as the pharmacological compounds that inhibit this signalling pathway as therapeutic intervention to prevent neuronal death

    3,4-Methylenedioxymethamphetamine enhances kainic acid convulsive susceptibility

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    Abstract Kainic acid (KA) causes seizures and neuronal loss in the hippocampus. The present study investigated whether a recreational schedule of 3,4-methylenedioxymethamphetamine (MDMA) favours the development of a seizure state in a model of KA-induced epilepsy and potentiates the toxicity profile of KA (20 or 30 mg/kg). Adolescent male C57BL/6 mice received saline or MDMA t.i.d. (s.c. every 3 h), on 1 day a week, for 4 consecutive weeks. Twenty-four hours after the last MDMA exposure, the animals were injected with saline or KA (20 or 30 mg/kg). After this injection, we evaluated seizures, hippocampal neuronal cell death, microgliosis, astrogliosis, and calcium binding proteins. MDMA pretreatment, by itself, did not induce neuronal damage but increased seizure susceptibility in all KA treatments and potentiated the presence of Fluoro-Jade-positive cells in CA1. Furthermore, MDMA, like KA, significantly decreased parvalbumin levels in CA1 and dentate gyrus, where it potentiated the effects of KA. The amphetamine derivative also promoted a transient decrease in calbindin and calretinin levels, indicative of an abnormal neuronal discharge. In addition, treatment of cortical neurons with MDMA (1050 μM) for 6 or 48 h significantly increased basal Ca2 +, reduced basal Na+ levels and potentiated kainate response. These results indicate that MDMA potentiates KA-induced neurodegeneration and also increases KA seizure susceptibility. The mechanism proposed includes changes in Calcium Binding Proteins expression, probably due to the disruption of intracellular ionic homeostasis, or/and an indirect effect through glutamate release

    Involvement of JNK1 in neuronal polarization during brain development

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    The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS

    The Preclinical discovery and development of opicapone for the treatment of Parkinson's Disease

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    Introduction: Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson's disease (PD) associated with L-DOPA / L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favours more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. Areas covered: This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data were extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000-2019). Clinical and post-marketing data were also evaluated. Expert opinion: OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Abbreviations: 3-OMD, 3-O-methyldopa; 6-OHDA, 6-hydroxydopamine; BG, basal ganglia; COMT, Catechol-O-methyltransferase; DDI, decarboxylase inhibitors; ENT, Entacapone; FDA, Food and Drug Administration; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OPC, Opicapone; PD, Parkinson's disease; TOL, Tolcapone; GDNF, Glial cell-line-derived neurotrophic factor; NTN, neurturin; ICV, Intracerebroventricular; PDUFA, Prescription Drug User Fees Act; EMA, European Medicine Administration; AE, Adverse event BG, Basal ganglia. QD, once a day

    Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways.

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    The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks

    The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet

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    The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology

    Epigallocatechin-3-gallate PEGylated poly(lactic-co-glycolic) acid nanoparticles mitigate striatal pathology and motor deficits in 3-nitropropionic acid intoxicated mice

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    Huntington's disease (HD) is a debilitating neurodegenerative disease that affects around 5-10/100,000 individuals in developed countries. It is caused by genetic alterations in the huntingtin (htt) gene. Efforts are being made to find treatments which will correct the genetic alterations or their pathophysiological consequences associated with HD,3 however none of these options are yet available to patients. Thus, therapies that address and ameliorate the symptomatology of HD, which include motor dysfunction and a wide range of behavioural disturbances, are also needed. Epigallocatechin-3-gallate (EGCG) is a powerful compound extracted from the green tea plant that may possess beneficial effects for HD patients, but whose therapeutic success is limited because of its chemical instability. Here, we show that protective encapsulation of EGCG rendered it much more efficient in attenuating motor deficits and depression-like behaviour in a mice model of HD-like neurodegeneration. Importantly, behavioural improvement was also associated with a reduction of neuronal damage. These results, together with our previous findings using nanoparticle-encapsulated EGCG in mouse models of Alzheimer's disease and epilepsy, highlight their potential effectiveness for symptomatic treatment of neurodegenerative diseases
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