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

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

JNK isoforms control adult mammal hippocampal neurogenesis

[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

Role of JNK in neurodegenerative diseases

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

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function

Background and aim: The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods: Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP‑ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results: Our studies demonstrated that HFD in Jnk3-/- lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions: Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.This work was supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2017-84283-R to AC), the Generalitat de Catalunya (2014SGR-525 to CA) and CIBERNED (Grant CB06/05/2004 to AC).S

Involvement of JNK1 in neuronal polarization during brain development

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

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

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

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

Protein tyrosine phosphatase 1B (PTP1B) as a potential therapeutic target for neurological disorders

Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.This work was supported by funds from the Spanish Ministerio de Ciencia e Innovación (SAF2017-84283‑R and PID2021-123462OB-I00 to AC and CA), the Generalitat de Catalunya (2014SGR‑525 to CA), CIBERNED (Grant CB06/05/2004 to AC) and AARG-NTF-22-924702, (MB). Jordi Olloquequi and Miren Ettcheto are Serra Húnter fellows.Peer reviewe

CDK11 Promotes Cytokine-Induced Apoptosis in Pancreatic Beta Cells Independently of Glucose Concentration and Is Regulated by Inflammation in the NOD Mouse Model

Background: Pancreatic islets are exposed to strong pro-apoptotic stimuli: inflammation and hyperglycemia, during the progression of the autoimmune diabetes (T1D). We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose. Methods: We studied T1D pathogenesis in NOD mice hemideficient for CDK11 (N-HTZ), and, in N-HTZ deficient for Cyclin D3 (K11HTZ-D3KO), in comparison to their respective controls (N-WT and K11WT-D3KO). Moreover, we exposed pancreatic islets to either pro-inflammatory cytokines in the presence of increasing glucose concentrations, or Thapsigargin, an Endoplasmic Reticulum (ER)-stress inducing agent, and assessed apoptotic events. The expression of key ER-stress markers (Chop, Atf4 and Bip) was also determined. Results: N-HTZ mice were significantly protected against T1D, and NS-HTZ pancreatic islets exhibited an impaired sensitivity to cytokine-induced apoptosis, regardless of glucose concentration. However, thapsigargin-induced apoptosis was not altered. Furthermore, CDK11 hemideficiency did not attenuate the exacerbation of T1D caused by Cyclin D3 deficiency. Conclusions: This study is the first to report that CDK11 is repressed in T1D as a protection mechanism against inflammation-induced apoptosis and suggests that CDK11 lies upstream Cyclin D3 signaling. We unveil the CDK11/Cyclin D3 tandem as a new potential intervention target in T1D