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Neuroprotection: Rescue from Neuronal Death in the Brain 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 May 2022) | Viewed by 40055

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Prof. Dr. Bae Hwan Lee

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Department of Physiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Interests: mechanisms of pain; neural injury; functional recovery; higher order functions of the brain; science of emotion and sensibility
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Dear Colleagues,

The brain is vulnerable to injury. Following injury in the brain, apoptosis or necrosis could easily occur, leading to various functional disabilities. Neuronal death is associated with a number of neurological disorders including hypoxic ischemia, epileptic seizures, and neurodegenerative diseases.

The injury to the brain is considered responsible for alterations in neurotransmission processes, resulting in functional changes. Oxidative stress produced by reactive oxygen species has been shown to be related to neuron death in traumatic injury, stroke, and neurodegenerative diseases. Therefore, scavenging or decreasing free radicals may be crucial for preventing neural tissues from harmful adverse effects in the brain. Neurotrophic factors, bioactive compounds, dietary nutrients, or cell engineering may ameliorate the pathological processes related to neuronal death or neurodegeneration and appear beneficial for improving neuroprotection. As a result of neuronal death or neuroprotection, the brain undergoes activity-dependent long-lasting changes in synaptic transmission, which is also known as functional plasticity.

Neuroprotection, implying the rescue from neuronal death, is now becoming one of the major global health concerns. This Special Issue attempts to explore the recent advances in neuroprotection related to the brain. For this Special Issue, we welcome original research or review papers demonstrating the mechanisms of neuroprotection against brain injury using in vivo or in vitro models of animals as well as in clinical settings. The conclusions of the paper should be supported by sufficient data or evidence.

Prof. Dr. Bae Hwan Lee
Guest Editor

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Keywords

neuroprotection
brain injury
neuronal death
neurodegeneration
neurological disorders
functional plasticity
Neuroendocrinology
neuroendocrine

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 185 KiB

Open AccessEditorial

Neuroprotection: Rescue from Neuronal Death in the Brain 2.0

by Bae Hwan Lee

Int. J. Mol. Sci. 2023, 24(6), 5273; https://doi.org/10.3390/ijms24065273 - 9 Mar 2023

Cited by 1 | Viewed by 1241

Abstract

The brain is vulnerable to endogenous or exogenous injuries [...] Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

Research

Jump to: Editorial, Review

16 pages, 5235 KiB

Open AccessArticle

Regulation and Role of Neuron-Derived Hemoglobin in the Mouse Hippocampus

by Yujiao Lu, Jing Wang, Fulei Tang, Uday P. Pratap, Gangadhara R. Sareddy, Krishnan M. Dhandapani, Ana Capuano, Zoe Arvanitakis, Ratna K. Vadlamudi and Darrell W. Brann

Int. J. Mol. Sci. 2022, 23(10), 5360; https://doi.org/10.3390/ijms23105360 - 11 May 2022

Cited by 7 | Viewed by 2701

Abstract

Hemoglobin (Hb) is the oxygen transport protein in erythrocytes. In blood, Hb is a tetramer consisting of two Hb-alpha (Hb-α) chains and two Hb-beta (Hb-β) chains. A number of studies have also shown that Hb-α is also expressed in neurons in both the rodent and human brain. In the current study, we examined for age-related regulation of neuronal Hb-α and hypoxia in the hippocampus and cerebral cortex of intact male and female mice. In addition, to confirm the role and functions of neuronal Hb-α, we also utilized lentivirus CRISPR interference-based Hb-α knockdown (Hb-α CRISPRi KD) in the non-ischemic and ischemic mouse hippocampus and examined the effect on neuronal oxygenation, as well as induction of hypoxia-inducible factor-1α (HIF-1α) and its downstream pro-apoptotic factors, PUMA and NOXA, and on neuronal survival and neurodegeneration. The results of the study revealed an age-related decrease in neuronal Hb-α levels and correlated increase in hypoxia in the hippocampus and cortex of intact male and female mice. Sex differences were observed with males having higher neuronal Hb-α levels than females in all brain regions at all ages. In vivo Hb-α CRISPRi KD in the mouse hippocampus resulted in increased hypoxia and elevated levels of HIF-1α, PUMA and NOXA in the non-ischemic and ischemic mouse hippocampus, effects that were correlated with a significant decrease in neuronal survival and increased neurodegeneration. As a whole, these findings indicate that neuronal Hb-α decreases with age in mice and has an important role in regulating neuronal oxygenation and neuroprotection. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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15 pages, 4317 KiB

Open AccessArticle

Role of Bevacizumab on Vascular Endothelial Growth Factor in Apolipoprotein E Deficient Mice after Traumatic Brain Injury

by Tiziana Genovese, Daniela Impellizzeri, Ramona D’Amico, Roberta Fusco, Alessio Filippo Peritore, Davide Di Paola, Livia Interdonato, Enrico Gugliandolo, Rosalia Crupi, Rosanna Di Paola, Salvatore Cuzzocrea, Marika Cordaro and Rosalba Siracusa

Int. J. Mol. Sci. 2022, 23(8), 4162; https://doi.org/10.3390/ijms23084162 - 9 Apr 2022

Cited by 15 | Viewed by 2378

Abstract

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB). Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI and to be overexpressed in the absence of apolipoprotein E (ApoE). Bevacizumab, a VEGF inhibitor, demonstrated neuroprotective activity in several models of TBI. However, the effects of bevacizumab on Apo-E deficient mice are not well studied. The present study aimed to evaluate VEGF expression and the effects of bevacizumab on BBB and neuroinflammation in ApoE^−/− mice undergoing TBI. Furthermore, for the first time, this study evaluates the effects of bevacizumab on the long-term consequences of TBI, such as atherosclerosis. The results showed that motor deficits induced by controlled cortical impact (CCI) were accompanied by increased brain edema and VEGF expression. Treatment with bevacizumab significantly improved motor deficits and significantly decreased VEGF levels, as well as brain edema compared to the control group. Furthermore, the results showed that bevacizumab preserves the integrity of the BBB and reduces the neuroinflammation induced by TBI. Regarding the effects of bevacizumab on atherosclerosis, it was observed for the first time that its ability to modulate VEGF in the acute phase of head injury prevents the acceleration of atherosclerosis. Therefore, the present study demonstrates not only the neuroprotective activity of bevacizumab but also its action on the vascular consequences related to TBI. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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14 pages, 3572 KiB

Open AccessArticle

Nimodipine Exerts Time-Dependent Neuroprotective Effect after Excitotoxical Damage in Organotypic Slice Cultures

by Urszula Hohmann, Chalid Ghadban, Tim Hohmann, Joshua Kleine, Miriam Schmidt, Christian Scheller, Christian Strauss and Faramarz Dehghani

Int. J. Mol. Sci. 2022, 23(6), 3331; https://doi.org/10.3390/ijms23063331 - 19 Mar 2022

Cited by 2 | Viewed by 2472

Abstract

During injuries in the central nervous system, intrinsic protective processes become activated. However, cellular reactions, especially those of glia cells, are frequently unsatisfactory, and further exogenous protective mechanisms are necessary. Nimodipine, a lipophilic L-type calcium channel blocking agent is clinically used in the treatment of aneurysmal subarachnoid haemorrhage with neuroprotective effects in different models. Direct effects of nimodipine on neurons amongst others were observed in the hippocampus as well as its influence on both microglia and astrocytes. Earlier studies proposed that nimodipine protective actions occur not only via calcium channel-mediated vasodilatation but also via further time-dependent mechanisms. In this study, the effect of nimodipine application was investigated in different time frames on neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Nimodipine, but not nifedipine if pre-incubated for 4 h or co-applied with NMDA, was protective, indicating time dependency. Since blood vessels play no significant role in our model, intrinsic brain cell-dependent mechanisms seems to strongly be involved. We also examined the effect of nimodipine and nifedipine on microglia survival. Nimodipine seem to be a promising agent to reduce secondary damage and reduce excitotoxic damage. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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27 pages, 5809 KiB

Open AccessArticle

7,8-Dihydroxiflavone Maintains Retinal Functionality and Protects Various Types of RGCs in Adult Rats with Optic Nerve Transection

by Alejandro Gallego-Ortega, Beatriz Vidal-Villegas, María Norte-Muñoz, Manuel Salinas-Navarro, Marcelino Avilés-Trigueros, María Paz Villegas-Pérez and Manuel Vidal-Sanz

Int. J. Mol. Sci. 2021, 22(21), 11815; https://doi.org/10.3390/ijms222111815 - 30 Oct 2021

Cited by 13 | Viewed by 2515

Abstract

To analyze the neuroprotective effects of 7,8-Dihydroxyflavone (DHF) in vivo and ex vivo, adult albino Sprague-Dawley rats were given a left intraorbital optic nerve transection (IONT) and were divided in two groups: One was treated daily with intraperitoneal (ip) DHF (5 mg/kg) (n = 24) and the other (n = 18) received ip vehicle (1% DMSO in 0.9% NaCl) from one day before IONT until processing. At 5, 7, 10, 12, 14, and 21 days (d) after IONT, full field electroretinograms (ERG) were recorded from both experimental and one additional naïve-control group (n = 6). Treated rats were analyzed 7 (n = 14), 14 (n = 14) or 21 d (n = 14) after IONT, and the retinas immune stained against Brn3a, Osteopontin (OPN) and the T-box transcription factor T-brain 2 (Tbr2) to identify surviving retinal ganglion cells (RGCs) (Brn3a⁺), α-like (OPN⁺), α-OFF like (OPN⁺Brn3a⁺) or M4-like/α-ON sustained RGCs (OPN⁺Tbr⁺). Naïve and right treated retinas showed normal ERG recordings. Left vehicle-treated retinas showed decreased amplitudes of the scotopic threshold response (pSTR) (as early as 5 d), the rod b-wave, the mixed response and the cone response (as early as 10 d), which did not recover with time. In these retinas, by day 7 the total numbers of Brn3a⁺RGCs, OPN⁺RGCs and OPN⁺Tbr2⁺RGCs decreased to less than one half and OPN⁺Brn3a⁺RGCs decreased to approximately 0.5%, and Brn3a⁺RGCs showed a progressive loss with time, while OPN⁺RGCs and OPN⁺Tbr2⁺RGCs did not diminish after seven days. Compared to vehicle-treated, the left DHF-treated retinas showed significantly greater amplitudes of the pSTR, normal b-wave values and significantly greater numbers of OPN⁺RGCs and OPN⁺Tbr2⁺RGCs for up to 14 d and of Brn3a⁺RGCs for up to 21 days. DHF affords significant rescue of Brn3a⁺RGCs, OPN⁺RGCs and OPN⁺Tbr2⁺RGCs, but not OPN⁺Brn3a⁺RGCs, and preserves functional ERG responses after IONT. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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17 pages, 3037 KiB

Open AccessArticle

Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons

by Huiling Gao, Wei Zheng, Cheng Li and He Xu

Int. J. Mol. Sci. 2021, 22(21), 11582; https://doi.org/10.3390/ijms222111582 - 27 Oct 2021

Cited by 7 | Viewed by 2763

Abstract

Hydrogen peroxide (H₂O₂)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H₂O₂. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H₂O₂. We propose that ApoE alleviates H₂O₂-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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18 pages, 5592 KiB

Open AccessArticle

The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease

by Md Ezazul Haque, Shofiul Azam, Mahbuba Akther, Duk-Yeon Cho, In-Su Kim and Dong-Kug Choi

Int. J. Mol. Sci. 2021, 22(9), 4674; https://doi.org/10.3390/ijms22094674 - 28 Apr 2021

Cited by 16 | Viewed by 3846

Abstract

The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test–assessed motor performance and improved Y-maze test–assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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Review

Jump to: Editorial, Research

34 pages, 2015 KiB

Open AccessReview

Demystifying the Neuroprotective Role of Neuropeptides in Parkinson’s Disease: A Newfangled and Eloquent Therapeutic Perspective

by Tapan Behl, Piyush Madaan, Aayush Sehgal, Sukhbir Singh, Hafiz A. Makeen, Mohammed Albratty, Hassan A. Alhazmi, Abdulkarim M. Meraya and Simona Bungau

Int. J. Mol. Sci. 2022, 23(9), 4565; https://doi.org/10.3390/ijms23094565 - 20 Apr 2022

Cited by 9 | Viewed by 4216

Abstract

Parkinson’s disease (PD) refers to one of the eminently grievous, preponderant, tortuous nerve-cell-devastating ailments that markedly impacts the dopaminergic (DArgic) nerve cells of the midbrain region, namely the substantia nigra pars compacta (SN-PC). Even though the exact etiopathology of the ailment is yet indefinite, the existing corroborations have suggested that aging, genetic predisposition, and environmental toxins tremendously influence the PD advancement. Additionally, pathophysiological mechanisms entailed in PD advancement encompass the clumping of α-synuclein inside the lewy bodies (LBs) and lewy neurites, oxidative stress, apoptosis, neuronal-inflammation, and abnormalities in the operation of mitochondria, autophagy lysosomal pathway (ALP), and ubiquitin–proteasome system (UPS). The ongoing therapeutic approaches can merely mitigate the PD-associated manifestations, but until now, no therapeutic candidate has been depicted to fully arrest the disease advancement. Neuropeptides (NPs) are little, protein-comprehending additional messenger substances that are typically produced and liberated by nerve cells within the entire nervous system. Numerous NPs, for instance, substance P (SP), ghrelin, neuropeptide Y (NPY), neurotensin, pituitary adenylate cyclase-activating polypeptide (PACAP), nesfatin-1, and somatostatin, have been displayed to exhibit consequential neuroprotection in both in vivo and in vitro PD models via suppressing apoptosis, cytotoxicity, oxidative stress, inflammation, autophagy, neuronal toxicity, microglia stimulation, attenuating disease-associated manifestations, and stimulating chondriosomal bioenergetics. The current scrutiny is an effort to illuminate the neuroprotective action of NPs in various PD-experiencing models. The authors carried out a methodical inspection of the published work procured through reputable online portals like PubMed, MEDLINE, EMBASE, and Frontier, by employing specific keywords in the subject of our article. Additionally, the manuscript concentrates on representing the pathways concerned in bringing neuroprotective action of NPs in PD. In sum, NPs exert substantial neuroprotection through regulating paramount pathways indulged in PD advancement, and consequently, might be a newfangled and eloquent perspective in PD therapy. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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26 pages, 1602 KiB

Open AccessReview

Mechanistic Insights Expatiating the Redox-Active-Metal-Mediated Neuronal Degeneration in Parkinson’s Disease

by Tapan Behl, Piyush Madaan, Aayush Sehgal, Sukhbir Singh, Md Khalid Anwer, Hafiz A. Makeen, Mohammed Albratty, Syam Mohan and Simona Bungau

Int. J. Mol. Sci. 2022, 23(2), 678; https://doi.org/10.3390/ijms23020678 - 8 Jan 2022

Cited by 16 | Viewed by 3778

Abstract

Parkinson’s disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), autophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochondrial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations, for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and conveyance of oxygen (O₂). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood–brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein aggregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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17 pages, 1676 KiB

Open AccessReview

Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection

by Kyung Hee Lee, Myeounghoon Cha and Bae Hwan Lee

Int. J. Mol. Sci. 2021, 22(24), 13315; https://doi.org/10.3390/ijms222413315 - 10 Dec 2021

Cited by 56 | Viewed by 6592

Abstract

To counteract oxidative stress and associated brain diseases, antioxidant systems rescue neuronal cells from oxidative stress by neutralizing reactive oxygen species and preserving gene regulation. It is necessary to understand the communication and interactions between brain cells, including neurons, astrocytes and microglia, to understand oxidative stress and antioxidant mechanisms. Here, the role of glia in the protection of neurons against oxidative injury and glia–neuron crosstalk to maintain antioxidant defense mechanisms and brain protection are reviewed. The first part of this review focuses on the role of glia in the morphological and physiological changes required for brain homeostasis under oxidative stress and antioxidant defense mechanisms. The second part focuses on the essential crosstalk between neurons and glia for redox balance in the brain for protection against oxidative stress. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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34 pages, 3279 KiB

Open AccessReview

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

by Tapan Behl, Piyush Madaan, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Saurabh Bhatia, Ahmed Al-Harrasi, Sridevi Chigurupati, Ibrahim Alrashdi and Simona Gabriela Bungau

Int. J. Mol. Sci. 2021, 22(18), 10161; https://doi.org/10.3390/ijms221810161 - 21 Sep 2021

Cited by 43 | Viewed by 5476

Abstract

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

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