International Journal of Molecular Sciences

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13 pages, 2644 KiB

Open AccessArticle

Cytoskeleton Protein EB3 Contributes to Dendritic Spines Enlargement and Enhances Their Resilience to Toxic Effects of Beta-Amyloid

by Ekaterina Pchitskaya, Anastasiya Rakovskaya, Margarita Chigray and Ilya Bezprozvanny

Int. J. Mol. Sci. 2022, 23(4), 2274; https://doi.org/10.3390/ijms23042274 - 18 Feb 2022

Cited by 3 | Viewed by 2320

Abstract

EB3 protein is expressed abundantly in the nervous system and transiently enters the dendritic spines at the tip of the growing microtubule, which leads to spine enlargement. Nevertheless, the role of dynamic microtubules, and particularly EB3 protein, in synapse function is still elusive. [...] Read more.

EB3 protein is expressed abundantly in the nervous system and transiently enters the dendritic spines at the tip of the growing microtubule, which leads to spine enlargement. Nevertheless, the role of dynamic microtubules, and particularly EB3 protein, in synapse function is still elusive. By manipulating the EB3 expression level, we have shown that this protein is required for a normal dendritogenesis. Nonetheless, EB3 overexpression also reduces hippocampal neurons dendritic branching and total dendritic length. This effect likely occurs due to the speeding neuronal development cycle from dendrite outgrowth to the step when dendritic spines are forming. Implementing direct morphometric characterization of dendritic spines, we showed that EB3 overexpression leads to a dramatic increase in the dendritic spine head area. EB3 knockout oppositely reduces spine head area and increases spine neck length and spine neck/spine length ratio. The same effect is observed in conditions of amyloid-beta toxicity, modeling Alzheimer`s disease. Neck elongation is supposed to be a common detrimental effect on the spine’s shape, which makes them biochemically and electrically less connected to the dendrite. EB3 also potentiates the formation of presynaptic protein Synapsin clusters and CaMKII-alpha preferential localization in spines rather than in dendrites of hippocampal neurons, while its downregulation has an opposite effect and reduces the size of presynaptic protein clusters Synapsin and PSD95. EB3′s role in spine development and maturation determines its neuroprotective effect. EB3 overexpression makes dendritic spines resilient to amyloid-beta toxicity, restores altered PSD95 clustering, and reduces CaMKII-alpha localization in spines observed in this pathological state. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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12 pages, 29532 KiB

Open AccessArticle

Conversion of Human Fibroblasts into Induced Neural Stem Cells by Small Molecules

by Donghui Liu, Grigori Rychkov, Plinio Hurtado, Hai-Yun Luo, Tao Zhang, Larisa Bobrovskaya and Xin-Fu Zhou

Int. J. Mol. Sci. 2022, 23(3), 1740; https://doi.org/10.3390/ijms23031740 - 3 Feb 2022

Cited by 4 | Viewed by 2575

Abstract

Induced neural stem cells (iNSCs) reprogrammed from somatic cells hold great potentials for drug discovery, disease modelling and the treatment of neurological diseases. Although studies have shown that human somatic cells can be converted into iNSCs by introducing transcription factors, these iNSCs are [...] Read more.

Induced neural stem cells (iNSCs) reprogrammed from somatic cells hold great potentials for drug discovery, disease modelling and the treatment of neurological diseases. Although studies have shown that human somatic cells can be converted into iNSCs by introducing transcription factors, these iNSCs are unlikely to be used for clinical application due to the safety concern of using exogenous genes and viral transduction vectors. Here, we report the successful conversion of human fibroblasts into iNSCs using a cocktail of small molecules. Furthermore, our results demonstrate that these human iNSCs (hiNSCs) have similar gene expression profiles to bona fide NSCs, can proliferate, and are capable of differentiating into glial cells and functional neurons. This study collectively describes a novel approach based on small molecules to produce hiNSCs from human fibroblasts, which may be useful for both research and therapeutic purposes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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11 pages, 1625 KiB

Open AccessCommunication

Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations

by Meewhi Kim and Ilya Bezprozvanny

Int. J. Mol. Sci. 2021, 22(24), 13600; https://doi.org/10.3390/ijms222413600 - 18 Dec 2021

Cited by 8 | Viewed by 2756

Abstract

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) [...] Read more.

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations—M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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16 pages, 1452 KiB

Open AccessArticle

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling

by Yulia V. Vakhitova, Tatiana S. Kalinina, Liana F. Zainullina, Anastasiya Yu. Lusta, Anna V. Volkova, Nikita V. Kudryashov, Tatiana A. Gudasheva, Alexander A. Shimshirt, Ilya A. Kadnikov, Mikhail V. Voronin and Sergei B. Seredenin

Int. J. Mol. Sci. 2021, 22(24), 13381; https://doi.org/10.3390/ijms222413381 - 13 Dec 2021

Cited by 12 | Viewed by 3259

Abstract

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel [...] Read more.

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB^706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB⁸¹⁶ in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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16 pages, 10488 KiB

Open AccessArticle

Effect of Central Administration of Brain-Derived Neurotrophic Factor (BDNF) on Behavior and Brain Monoamine Metabolism in New Recombinant Mouse Lines Differing by 5-HT_1A Receptor Functionality

by Darya Bazovkina, Vladimir Naumenko, Ekaterina Bazhenova and Elena Kondaurova

Int. J. Mol. Sci. 2021, 22(21), 11987; https://doi.org/10.3390/ijms222111987 - 5 Nov 2021

Cited by 10 | Viewed by 2188

Abstract

Experiments were carried out on recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines created by transferring a 102.73–118.83 Mbp fragment of chromosome 13, containing the 5-HT_1A receptor gene, from CBA or C57BL/6 strains to a C57BL/6 genetic background, correspondingly. We have recently [...] Read more.

Experiments were carried out on recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines created by transferring a 102.73–118.83 Mbp fragment of chromosome 13, containing the 5-HT_1A receptor gene, from CBA or C57BL/6 strains to a C57BL/6 genetic background, correspondingly. We have recently shown different levels of 5-HT1A receptor functionality in these mouse lines. The administration of BDNF (300 ng/mouse, i.c.v.) increased the levels of exploratory activity and intermale aggression only in B6-M76B mice, without affecting depressive-like behavior in both lines. In B6-M76B mice the behavioral alterations were accompanied by a decrease in the 5-HT_2A receptor functional activity and the augmentation of levels of serotonin and its main metabolite, 5-HIAA (5-hydroxyindoleacetic acid), in the midbrain. Moreover, the levels of dopamine and its main metabolites, HVA (homovanillic acid) and DOPAC (3,4-dihydroxyphenylacetic acid), were also elevated in the striatum of B6-M76B mice after BDNF treatment. In B6-M76C mice, central BDNF administration led only to a reduction in the functional activity of the 5-HT_1A receptor and a rise in DOPAC levels in the midbrain. The obtained data suggest the importance of the 102.73–118.83 Mbp fragment of mouse chromosome 13, which contains the 5-HT_1A receptor gene, for BDNF-induced alterations in behavior and the brain monoamine system. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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20 pages, 6197 KiB

Open AccessArticle

Anti-Inflammatory Activity of N-Docosahexaenoylethanolamine and N-Eicosapentaenoylethanolamine in a Mouse Model of Lipopolysaccharide-Induced Neuroinflammation

by Anna Tyrtyshnaia, Sophia Konovalova, Anatoly Bondar, Ekaterina Ermolenko, Ruslan Sultanov and Igor Manzhulo

Int. J. Mol. Sci. 2021, 22(19), 10728; https://doi.org/10.3390/ijms221910728 - 3 Oct 2021

Cited by 14 | Viewed by 3247

Abstract

The search for methods of cognitive impairment treatment and prevention in neurological and neurodegenerative diseases is an urgent task of modern neurobiology. It is now known that various diseases, accompanied by dementia, exhibit a pronounced neuroinflammation. Considering the significant docosahexaenoic and eicosapentaenoic polyunsaturated [...] Read more.

The search for methods of cognitive impairment treatment and prevention in neurological and neurodegenerative diseases is an urgent task of modern neurobiology. It is now known that various diseases, accompanied by dementia, exhibit a pronounced neuroinflammation. Considering the significant docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids’ therapeutic potential, we decided to investigate and compare anti-inflammatory activity of their N-acylethanolamine derivatives. As a result, we found that both N-docosahexaenoylethanolamine (synaptamide) and N-eicosapentaenoylethanolamine (EPEA) prevents an LPS-mediated increase in the proinflammatory cytokines TNF-α and IL-6 production in the SIM-A9 microglia culture. In an in vivo experiment, synaptamide reversed an increase in LPS-mediated hippocampal TNF-α and IL-1β, but EPEA did not. However, both compounds contributed to the microglia polarization towards the M2-phenotype. Synaptamide, rather than EPEA, inhibited the Iba-1-positive microglia staining area increase. However, both synaptamide and EPEA prevented the LPS-mediated astrogliosis. A study of BDNF immunoreactivity showed that synaptamide, but not EPEA, reversed an LPS-mediated decrease in BDNF production. Despite the more pronounced anti-inflammatory activity of synaptamide, both compounds were effective in maintaining a normal level of hippocampal long-term potentiation in neuroinflammation. The results indicate a high therapeutic potential for both compounds. However, some tests have shown higher activity of synaptamide compared to EPEA. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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21 pages, 5163 KiB

Open AccessArticle

Antistress Action of Melanocortin Derivatives Associated with Correction of Gene Expression Patterns in the Hippocampus of Male Rats Following Acute Stress

by Ivan B. Filippenkov, Vasily V. Stavchansky, Natalya Yu. Glazova, Elena A. Sebentsova, Julia A. Remizova, Liya V. Valieva, Natalia G. Levitskaya, Nikolai F. Myasoedov, Svetlana A. Limborska and Lyudmila V. Dergunova

Int. J. Mol. Sci. 2021, 22(18), 10054; https://doi.org/10.3390/ijms221810054 - 17 Sep 2021

Cited by 14 | Viewed by 3140

Abstract

Natural melanocortins (MCs) have been used in the successful development of drugs with neuroprotective properties. Here, we studied the behavioral effects and molecular genetic mechanisms of two synthetic MC derivatives-ACTH(4–7)PGP (Semax) and ACTH(6–9)PGP under normal and acute restraint stress (ARS) conditions. Administration of [...] Read more.

Natural melanocortins (MCs) have been used in the successful development of drugs with neuroprotective properties. Here, we studied the behavioral effects and molecular genetic mechanisms of two synthetic MC derivatives-ACTH(4–7)PGP (Semax) and ACTH(6–9)PGP under normal and acute restraint stress (ARS) conditions. Administration of Semax or ACTH(6–9)PGP (100 μg/kg) to rats 30 min before ARS attenuated ARS-induced behavioral alterations. Using high-throughput RNA sequencing (RNA-Seq), we identified 1359 differentially expressed genes (DEGs) in the hippocampus of vehicle-treated rats subjected to ARS, using a cutoff of >1.5 fold change and adjusted p-value (Padj) < 0.05, in samples collected 4.5 h after the ARS. Semax administration produced > 1500 DEGs, whereas ACTH(6–9)PGP administration led to <400 DEGs at 4.5 h after ARS. Nevertheless, ~250 overlapping DEGs were identified, and expression of these DEGs was changed unidirectionally by both peptides under ARS conditions. Modulation of the expression of genes associated with biogenesis, translation of RNA, DNA replication, and immune and nervous system function was produced by both peptides. Furthermore, both peptides upregulated the expression levels of many genes that displayed decreased expression after ARS, and vice versa, the MC peptides downregulated the expression levels of genes that were upregulated by ARS. Consequently, the antistress action of MC peptides may be associated with a correction of gene expression patterns that are disrupted during ARS. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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13 pages, 2208 KiB

Open AccessArticle

Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

by Eun-Hye Kim, Eun-Sun Kim, Donggeun Shin, Donghyun Kim, Sungbin Choi, Young-Jun Shin, Kyeong-A Kim, Dabi Noh, Ahmet B. Caglayan, G.K. Rajanikant, Arshad Majid and Ok-Nam Bae

Int. J. Mol. Sci. 2021, 22(14), 7495; https://doi.org/10.3390/ijms22147495 - 13 Jul 2021

Cited by 19 | Viewed by 3910

Abstract

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, [...] Read more.

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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Review

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30 pages, 1756 KiB

Open AccessReview

The Role of miRNAs in Dexmedetomidine’s Neuroprotective Effects against Brain Disorders

by Codrin-Constantin Burlacu, Maria-Adriana Neag, Andrei-Otto Mitre, Alexandru-Constantin Sirbu, Andrei-Vlad Badulescu and Anca-Dana Buzoianu

Int. J. Mol. Sci. 2022, 23(10), 5452; https://doi.org/10.3390/ijms23105452 - 13 May 2022

Cited by 19 | Viewed by 5507

Abstract

There are limited neuroprotective strategies for various central nervous system conditions in which fast and sustained management is essential. Neuroprotection-based therapeutics have become an intensively researched topic in the neuroscience field, with multiple novel promising agents, from natural products to mesenchymal stem cells, [...] Read more.

There are limited neuroprotective strategies for various central nervous system conditions in which fast and sustained management is essential. Neuroprotection-based therapeutics have become an intensively researched topic in the neuroscience field, with multiple novel promising agents, from natural products to mesenchymal stem cells, homing peptides, and nanoparticles-mediated agents, all aiming to significantly provide neuroprotection in experimental and clinical studies. Dexmedetomidine (DEX), an α2 agonist commonly used as an anesthetic adjuvant for sedation and as an opioid-sparing medication, stands out in this context due to its well-established neuroprotective effects. Emerging evidence from preclinical and clinical studies suggested that DEX could be used to protect against cerebral ischemia, traumatic brain injury (TBI), spinal cord injury, neurodegenerative diseases, and postoperative cognitive disorders. MicroRNAs (miRNAs) regulate gene expression at a post-transcriptional level, inhibiting the translation of mRNA into functional proteins. In vivo and in vitro studies deciphered brain-related miRNAs and dysregulated miRNA profiles after several brain disorders, including TBI, ischemic stroke, Alzheimer’s disease, and multiple sclerosis, providing emerging new perspectives in neuroprotective therapy by modulating these miRNAs. Experimental studies revealed that some of the neuroprotective effects of DEX are mediated by various miRNAs, counteracting multiple mechanisms in several disease models, such as lipopolysaccharides induced neuroinflammation, β-amyloid induced dysfunction, brain ischemic-reperfusion injury, and anesthesia-induced neurotoxicity models. This review aims to outline the neuroprotective mechanisms of DEX in brain disorders by modulating miRNAs. We address the neuroprotective effects of DEX by targeting miRNAs in modulating ischemic brain injury, ameliorating the neurotoxicity of anesthetics, reducing postoperative cognitive dysfunction, and improving the effects of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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26 pages, 2191 KiB

Open AccessReview

Stress-Induced Depression and Alzheimer’s Disease: Focus on Astrocytes

by Oleg V. Dolotov, Ludmila S. Inozemtseva, Nikolay F. Myasoedov and Igor A. Grivennikov

Int. J. Mol. Sci. 2022, 23(9), 4999; https://doi.org/10.3390/ijms23094999 - 30 Apr 2022

Cited by 37 | Viewed by 9174

Abstract

Neurodegenerative diseases and depression are multifactorial disorders with a complex and poorly understood physiopathology. Astrocytes play a key role in the functioning of neurons in norm and pathology. Stress is an important factor for the development of brain disorders. Here, we review data [...] Read more.

Neurodegenerative diseases and depression are multifactorial disorders with a complex and poorly understood physiopathology. Astrocytes play a key role in the functioning of neurons in norm and pathology. Stress is an important factor for the development of brain disorders. Here, we review data on the effects of stress on astrocyte function and evidence of the involvement of astrocyte dysfunction in depression and Alzheimer’s disease (AD). Stressful life events are an important risk factor for depression; meanwhile, depression is an important risk factor for AD. Clinical data indicate atrophic changes in the same areas of the brain, the hippocampus and prefrontal cortex (PFC), in both pathologies. These brain regions play a key role in regulating the stress response and are most vulnerable to the action of glucocorticoids. PFC astrocytes are critically involved in the development of depression. Stress alters astrocyte function and can result in pyroptotic death of not only neurons, but also astrocytes. BDNF-TrkB system not only plays a key role in depression and in normalizing the stress response, but also appears to be an important factor in the functioning of astrocytes. Astrocytes, being a target for stress and glucocorticoids, are a promising target for the treatment of stress-dependent depression and AD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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14 pages, 596 KiB

Open AccessReview

Computer-Based Drug Design of Positive Modulators of Store-Operated Calcium Channels to Prevent Synaptic Dysfunction in Alzheimer’s Disease

by Lernik Hunanyan, Viktor Ghamaryan, Ani Makichyan and Elena Popugaeva

Int. J. Mol. Sci. 2021, 22(24), 13618; https://doi.org/10.3390/ijms222413618 - 19 Dec 2021

Cited by 8 | Viewed by 3134

Abstract

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions [...] Read more.

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer’s disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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15 pages, 8228 KiB

Open AccessReview

PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides

by Lola Ugalde-Triviño and Margarita Díaz-Guerra

Int. J. Mol. Sci. 2021, 22(22), 12585; https://doi.org/10.3390/ijms222212585 - 22 Nov 2021

Cited by 40 | Viewed by 5168

Abstract

Therapies for stroke have remained elusive in the past despite the great relevance of this pathology. However, recent results have provided strong evidence that postsynaptic density protein-95 (PSD-95) can be exploited as an efficient target for stroke neuroprotection by strategies able to counteract [...] Read more.

Therapies for stroke have remained elusive in the past despite the great relevance of this pathology. However, recent results have provided strong evidence that postsynaptic density protein-95 (PSD-95) can be exploited as an efficient target for stroke neuroprotection by strategies able to counteract excitotoxicity, a major mechanism of neuronal death after ischemic stroke. This scaffold protein is key to the maintenance of a complex framework of protein interactions established at the postsynaptic density (PSD) of excitatory neurons, relevant to neuronal function and survival. Using cell penetrating peptides (CPPs) as therapeutic tools, two different approaches have been devised and advanced to different levels of clinical development. First, nerinetide (Phase 3) and AVLX-144 (Phase 1) were designed to interfere with the coupling of the ternary complex formed by PSD-95 with GluN2B subunits of the N-methyl-D-aspartate type of glutamate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS). These peptides reduced neurotoxicity derived from NMDAR overactivation, decreased infarct volume and improved neurobehavioral results in different models of ischemic stroke. However, an important caveat to this approach was PSD-95 processing by calpain, a pathological mechanism specifically induced by excitotoxicity that results in a profound alteration of survival signaling. Thus, a third peptide (TP95₄₁₄) has been recently developed to interfere with PSD-95 cleavage and reduce neuronal death, which also improves neurological outcome in a preclinical mouse model of permanent ischemia. Here, we review recent advancements in the development and characterization of PSD-95-targeted CPPs and propose the combination of these two approaches to improve treatment of stroke and other excitotoxicity-associated disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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16 pages, 1997 KiB

Open AccessReview

Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

by Vladimir Sukhorukov, Dmitry Voronkov, Tatiana Baranich, Natalia Mudzhiri, Alina Magnaeva and Sergey Illarioshkin

Int. J. Mol. Sci. 2021, 22(19), 10251; https://doi.org/10.3390/ijms221910251 - 23 Sep 2021

Cited by 25 | Viewed by 6233

Abstract

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become [...] Read more.

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Targeting of Neuroprotection)

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