Some of the most devastating and costly conditions in the world arise from neurological andneurodegenerative disorders. About one-third of the world's population suffers from neurologicaldiseases, including Parkinson's (PD) and Alzheimer's (AD) diseases, multiple sclerosis, epilepsy, spinal cord injury, and others. Symptoms may show early in childhood or substantially delayedin adolescence or young adulthood. Animal models are powerful tools aiding in understandingneurological pathophysiology towards developing neuroprotective strategies.So far, there are no well-established treatments for brain repair. Hence, neuroprotectionbecomes imperative. Synapses pose major targets for finding new neuroprotective agents.The aimof this topic is to share research addressing neuroprotective strategies for the brain, theirpossible pathways, and the use of pharmacological analogues. Four reviews are about hypoxia. Twochapters address themolecular bases of cognitive impairment in AD. Biochemical and physiologicalaspects of neuroprotective agents focusing on synaptic modifications, neuroprotection followingperinatal asphyxia, and pharmacological- and genetic-targeting strategies for Alzheimer's and Parkinson's diseases are reviewed.Fil: Otero losada, Matilde Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Wandosell, Francisco G.. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Científicas; EspañaFil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentin

Capani, Francisco

Otero losada, Matilde Estela

Wandosell, Francisco G.

Frontiers in Synaptic Neuroscience

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

EDITORIALpublished: 03 September 2021doi: 10.3389/fnsyn.2021.746487Frontiers in Synaptic Neuroscience | www.frontiersin.org 1 September 2021 | Volume 13 | Article 746487Edited and reviewed by:P. Jesper Sjöström,McGill University, Canada*Correspondence:Matilde Otero-Losadamolly1063@gmail.comReceived: 23 July 2021Accepted: 05 August 2021Published: 03 September 2021Citation:Otero-Losada M, Wandosell FG andCapani F (2021) Editorial:Neuroprotection in Synaptic SignallingDuring Neurological Disorders.Front. Synaptic Neurosci. 13:746487.doi: 10.3389/fnsyn.2021.746487Editorial: Neuroprotection in SynapticSignalling During NeurologicalDisordersMatilde Otero-Losada 1*, Francisco G. Wandosell 2 and Francisco Capani 1,31Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional deInvestigaciones Científicas y Técnicas, CAECIHS.UAI-CONICET, Buenos Aires, Argentina, 2Centro de Biología MolecularSevero Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CSIC-UAM y Centro deInvestigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain, 3Centro deInvestigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía, Pontificia UniversidadCatólica Argentina (UCA), Buenos Aires, ArgentinaKeywords: synapse, intracellular pathway, translational medicine, neurodegeneration, pharmacological strategiesEditorial on the Research TopicNeuroprotection in Synaptic Signalling During Neurological DisordersSome of the most devastating and costly conditions in the world arise from neurological andneurodegenerative disorders. About one-third of the world’s population suffers from neurologicaldiseases, including Parkinson’s (PD) and Alzheimer’s (AD) diseases, multiple sclerosis, epilepsy,spinal cord injury, and others. Symptoms may show early in childhood or substantially delayedin adolescence or young adulthood. Animal models are powerful tools aiding in understandingneurological pathophysiology towards developing neuroprotective strategies.So far, there are no well-established treatments for brain repair. Hence, neuroprotectionbecomes imperative. Synapses pose major targets for finding new neuroprotective agents.The aim of this topic is to share research addressing neuroprotective strategies for the brain, theirpossible pathways, and the use of pharmacological analogues. Four reviews are about hypoxia. Twochapters address themolecular bases of cognitive impairment in AD. Biochemical and physiologicalaspects of neuroprotective agents focusing on synaptic modifications, neuroprotection followingperinatal asphyxia, and pharmacological- and genetic-targeting strategies for Alzheimer’s andParkinson’s diseases are reviewed.Synaptoprotection in Perinatal Asphyxia: An Experimental Approach of Herrera et al., amini review on this obstetrical complication occurring when the oxygen supply to the newbornis interrupted, associated with high morbimortality. Around 25% of PA survivor newbornsdevelop several neurodevelopmental disabilities because of severe synaptic damage. Synapticdysfunction embodies a putative target for neuroprotective strategies. Over the last years,therapeutic hypothermia, the only treatment available, has shown positive results in the clinic[(Barkhuizen et al., 2017; Herrera et al., 2017); (3)]. Several pharmacological agents are being testedin experimental or clinical trial studies to prevent synaptopathy. Synaptoprotection makes up apromising challenge for reducing incidental neurodevelopmental disorders associated with PA.The Renin–Angiotensin SystemModulates Dopaminergic Neurotransmission: A New Player onthe Scene of Kobiec et al. Parkinson’s disease (PD), an extrapyramidal neurodegenerative disorder,has become a major health problem, affecting 1% of the world population over 60 years old and3% of people beyond 80 years. The renin–angiotensin system (RAS), regulating blood pressureand body fluid balance, is also involved in autocrine and paracrine regulation of nigrostriataldopaminergic synapses (Capani et al., 2009; Labandeira-Garcia et al., 2017; Jackson et al., 2018;Lang and Espay, 2018; Simon et al., 2020). Dopamine depletion, as in PD, increases angiotensin IIOtero-Losada et al. Editorial: Neuroprotection in Synaptic Signallingexpression, which stimulates or inhibits dopamine synthesisand is released via angiotensin II type 1 or 2 receptors.Furthermore, the angiotensin II type 1 receptor inhibits D1receptor activation allosterically. Therefore, the RAS may havean important modulating role in the flow of information fromthe brain cortex to the basal ganglia.Nanoliposomes as a Therapeutic Tool for Alzheimer’sDisease of Ordóñez-Gutiérrez and Wandosell. This chaptercovers promising therapeutic avenues for AD treatment.Nanoliposome therapies for AD, still in clinical trials, arediscussed, and nanoliposomes-bound anti-amyloid-beta(Aβ) peptide antibodies are presented. Extracellular Aβdeposits (senile plaques) and intracellular neurofibrillarytangles of hyperphosphorylated Tau protein are two majorneuropathological AD hallmarks. Brain and peripheral Aβ levelsare in equilibrium. Enhancing peripheral clearance might reducebrain Aβ level, known as the sink effect. Nanoparticles may havedifficulty in crossing the blood-brain barrier unless derivatized.Several nanoparticles’ derivatives have been proposed, carryingantibodies against Aβ (Carradori et al., 2018).An Assessment of Melatonin’s Therapeutic Value in theHypoxic-Ischemic Encephalopathy of the Newborn of Cardinali.Hypoxic-ischemic encephalopathy is one of the most frequentcauses of brain injury in the newborn. According to the WorldHealth Organisation, for every day in 2015, 16,000 children agedunder five died (World Health Organization, 2015). Melatoninhas impaired chronic mechanisms of neuronal death. In animalmodels, and in a limited number of clinical studies, melatoninincreased the level of protection developed by hypothermia innewborn asphyxia (Xu et al., 2017). This review summarisestherapeutic strategies, assessing the role of melatonin as apotentially relevant therapeutic tool to cover the hypoxia-ischemia (HI) phase and the secondary and tertiary phasesfollowing a HI insult.Fetal Neuroprotective Strategies: Therapeutic Agents andTheir Underlying Synaptic Pathways of Elsayed et al. Emergingevidence suggests that melatonin and N-acetyl-L-cysteine(NAC) may also serve as novel putative foetal neuroprotectivecandidates. Melatonin has important anti-inflammatory andantioxidant properties and is a known mediator of synapticplasticity and neuronal generation. While NAC acts as anantioxidant and a precursor to glutathione, it also modulates theglutamate system. Glutamate excitotoxicity and dysregulationcan induce perinatal preterm brain injury through damage tomaturing oligodendrocytes and neurons. The improved drugefficacy and delivery of the dendrimer-bound NAC conjugateprovides an opportunity for enhanced pharmacologicalintervention. Recent literature on the synaptic pathwaysunderlying NAC and melatonin effects is reviewed, discussingthe current gaps in knowledge, and proposing future directionsfor foetal neuroprotection (Dean et al., 2011).Current therapies for neonatal hypoxic-ischaemic andinfection-sensitised hypoxic-ischaemic brain damage of Tetorouet al. Therapeutic hypothermia is the only approved treatmentfor neonatal HI. However, the number of HI infants neededto treat with hypothermia for one to be saved from death ordisability at age of 18–22 months, is ∼6–7, highlighting theurge for alternative or additional strategies. The authors discussthe mechanisms of HI injury to the immature brain and thenew experimental treatments studied for neonatal HI andinfection-sensitised neonatal HI (Nair and Kumar, 2018).Early Effects of Aβ Oligomers on Dendritic Spine Dynamicsand Arborization in Hippocampal Neurons of Ortiz-Sanz et al.Aβ oligomers induce synaptic damage early in Alzheimer’sdisease. An open question for understanding AD pathologyis how soluble Aβ contributes to dendritic spine loss anddendritic simplification, as there are a large number ofputative Aβ receptors (Jarosz-Griffiths et al., 2016). The authorsexamined the acute effects of soluble Aβ42 on spine dynamics,dendritic alteration, and signalling pathways, using hippocampalneurons, and high-resolution imaging followed by algorithm-based evaluation of spine changes and alterations of dendriticarborization. Acute Aβ oligomers increased spine density bymechanisms involving integrin β1 and CaMKII signalling,promoting dendritic complexity in CA1 hippocampal neurons.Next coming, neuroprotection strategies might point toimmunotherapy. The FDA, through an Accelerated ApprovalProgram, has recently approved an anti-amyloid antibodyas the first new option in AD treatment. Yet, improvedhuman-akin accurate experimental models are still missing.Intensive genetic manipulation, like the need to introducethree dominant mutations to have an AD-like mice phenotype,makes the model controversial. Besides, many promisingtreatments in experimental stroke and head and spinal cordinjury have failed in clinical trials. The road to identifyingsuccessful neuroprotection approaches is still to be walkedthrough research.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.REFERENCESBarkhuizen, M., van den Hove, D. L. A., Vles, J. S. H., Steinbusch, H. W. M.,Kramer, B.W., and Gavilanes, A.W. D. (2017). Twenty-five years of research onglobal asphyxia in the immature rat brain. Neurosci. Biobehav. R. 75, 166–182.doi: 10.1016/j.neubiorev.2017.01.042Capani, F., Saraceno, G. E., Botti, V., Aon-Bertolino, L., Madureirade Oliveira, D., Barreto, G., et al. (2009). Protein ubiquitination inpostsynaptic densities after hypoxia in rat neostriatum is blocked byhypothermia. Exp. Neurol. 219, 404–413. doi: 10.1016/j.expneurol.2009.06.007Carradori, D., Balducci, C., Re, F., Brambilla, D., Le Droumaguet, B.,Flores, O., et al. (2018). Antibody-functionalized polymer nanoparticleleading to memory recovery in Alzheimer’s disease-like transgenicmouse model. Nanomedicine 14, 609–618. doi: 10.1016/j.nano.2017.12.006Frontiers in Synaptic Neuroscience | www.frontiersin.org 2 September 2021 | Volume 13 | Article 746487Otero-Losada et al. Editorial: Neuroprotection in Synaptic SignallingDean, O., Giorlando, F., and Berk, M. (2011). N-acetylcysteine in psychiatry:current therapeutic evidence and potential mechanisms of action. J. PsychiatryNeurosci. 36, 78–86. doi: 10.1503/jpn.100057Herrera, M. I., Otero-Losada, M., Udovin, L. D., Kusnier, C., Kölliker-Frers, R.,de Souza, W., et al. (2017). Could perinatal asphyxia induce a synaptopathy?New highlights from an experimental model. Neural Plast. 2017:3436943.doi: 10.1155/2017/3436943Jackson, L., Eldahshan, W., Fagan, S. C., and Ergul, A. (2018). Within the brain: therenin angiotensin system. Int. J. Mol. Sci. 19:876. doi: 10.3390/ijms19030876Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V., and Hooper, N.M. (2016). Amyloid-β receptors: the good, the bad, and the prionprotein. J. Biol. Chem. 291, 3174–3183. doi: 10.1074/jbc. r115.702704Labandeira-Garcia, J. L., Rodríguez-Perez, A. I., Garrido-Gil, P., Rodriguez-Pallares, J., Lanciego, J. L., and Guerra, M. J. (2017). Brain renin-angiotensin system and microglial polarization: implications for aging andneurodegeneration. Front. Aging Neurosci. 9:129. doi: 10.3389/fnagi.2017.00129Lang, A. E., and Espay, A. J. (2018). Disease modification in Parkinson’s disease:current approaches, challenges, and future considerations. J. Mov. Disord. 3,660–677. doi: 10.1002/mds.27360Nair, J., and Kumar, V. H. S. (2018). Current and emerging therapies in themanagement of hypoxic ischemic encephalopathy in neonates. Children 5:99.doi: 10.3390/children5070099Simon, D., Tanner, C., and Brundin, P. (2020). Parkinson disease epidemiology,pathology, genetics, and pathophysiology. Clin. Geriatr. Medie 36, 1–12.doi: 10.1016/j.cger.2019.08.002World Health Organization (2015). Health in 2015: From MDGs, MillenniumDevelopment Goals to SDGs, Sustainable Development Goals. Geneva: WorldHealth Organization.Xu, L. X., Lv, Y., Li, Y. H., Ding, X., Wang, Y., Han, X., et al. (2017). Melatoninalleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: the involvement of edema related proteins. BMCPediatr. 17:90. doi: 10.1186/s12887-017-0824-xConflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Otero-Losada, Wandosell and Capani. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Synaptic Neuroscience | www.frontiersin.org 3 September 2021 | Volume 13 | Article 746487

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Neuroprotection in Synaptic Signalling During Neurological Disorders

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Neuroprotection in Synaptic Signalling During Neurological Disorders

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