Bilberry and its main constituents have neuroprotective effects against retinal neuronal damage in vitro
 and in vivo

The objective of the present study was to prepare a stableivinjectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluatedin vitro. Forin vivoevaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4–8°C.In vivostudies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

Download Full-text

Agmatine Alleviates Epileptic Seizures and Hippocampal Neuronal Damage by Inhibiting Gasdermin D-Mediated Pyroptosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.627557 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xueying Li ◽

Jiahe Lin ◽

Yingjie Hua ◽

Jiaoni Gong ◽

Siqi Ding ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Neuronal Damage ◽

Epileptic Seizures ◽

Inhibitory Effect ◽

Enzyme Linked Immunosorbent Assay ◽

Nissl Staining ◽

Neuroprotective Effects ◽

Cellular Inflammation

Background: Epilepsy is a common neurological disease, and neuroinflammation is one of the main contributors to epileptogenesis. Pyroptosis is a type of pro-inflammatory cell death that is related to epilepsy. Agmatine, has anti-inflammatory properties and exerts neuroprotective effects against seizures. Our study investigated the effect of agmatine on the core pyroptosis protein GSDMD in the context of epilepsy.Methods: A chronic epilepsy model and BV2 microglial cellular inflammation model were established by pentylenetetrazole (PTZ)-induced kindling or lipopolysaccharide (LPS) stimulation. H&E and Nissl staining were used to evaluate hippocampal neuronal damage. The expression of pyroptosis and inflammasome factors was examined by western blotting, quantitative real-time PCR, immunofluorescence and enzyme-linked immunosorbent assay (ELISA).Results: Agmatine disrupted the kindling acquisition process, which decreased seizure scores and the incidence of full kindling and blocked hippocampal neuronal damage. In addition, agmatine increased BV2 microglial cell survival in vitro and alleviated seizures in vivo by suppressing the levels of PTZ-induced pyroptosis. Finally, the expression of TLR4, MYD88, phospho-IκBα, phospho-NF-κB and the NLRP3 inflammasome was significantly upregulated in LPS-induced BV2 microglial cells, while agmatine suppressed the expression of these proteins.Conclusions: Our results indicate that agmatine affects epileptogenesis and exerts neuroprotective effects by inhibiting neuroinflammation, GSDMD activation, and pyroptosis. The inhibitory effect of agmatine on pyroptosis was mediated by the suppression of the TLR4/MYD88/NF-κB/NLRP3 inflammasome pathway. Therefore, agmatine may be a potential treatment option for epilepsy.

Download Full-text

Propofol Exerts Greater Neuroprotection with Disodium Edetate than without It

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600532 ◽

2007 ◽

Vol 28 (2) ◽

pp. 354-366 ◽

Cited By ~ 12

Author(s):

Yoshinori Kotani ◽

Yoshimi Nakajima ◽

Tatsuya Hasegawa ◽

Masahiko Satoh ◽

Hisamitsu Nagase ◽

...

Keyword(s):

Neuronal Damage ◽

Cell Damage ◽

Infarct Volume ◽

Zinc Homeostasis ◽

Terminal Deoxynucleotidyl Transferase ◽

Causal Mechanism ◽

Neuroprotective Effects ◽

Disodium Edetate

The main objective of this study, on mice, was to compare the neuroprotective effects of propofol with those of propofol plus disodium edetate (propofol EDTA). We also administered propofol EDTA (0.005% (w/v) EDTA) to mice intravenously, and measured the changes in zinc concentrations occurring after permanent middle cerebral artery occlusion. In the in vivo study, propofol EDTA displayed stronger neuroprotective effects than propofol alone. Furthermore, we examined the neuroprotective effects of EDTA administered alone, and found that EDTA Na significantly reduced the infarct volume. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells in the ischemic penumbra was reduced more by propofol EDTA than by propofol alone. We performed in the in vitro study in five groups (aerobic, vehicle (control), propofol, EDTA, and propofol plus EDTA). Propofol and EDTA each protected PC12 cells against oxygen—glucose deprivation-induced cell damage, and the effect of propofol was increased by adding EDTA. Because the chelating action of EDTA was a potential causal mechanism, we examined the effect of propofol EDTA on intracerebral zinc homeostasis. When propofol EDTA was given intravenously 10 mins before cerebral ischemia, the zinc concentration decreased significantly in the cortical area, but not in the subcortex. In conclusion, (a) propofol provides neuroprotection against both in vivo and in vitro ischemic damage, and its effects are enhanced when EDTA is added; and (b) EDTA itself protects against ischemic neuronal damage, possibly, owing to its zinc-chelating action.

Download Full-text

Ginsenoside Rb1 Protects the Brain from Damage Induced by Epileptic Seizure via Nrf2/ARE Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000486768 ◽

2018 ◽

Vol 45 (1) ◽

pp. 212-225 ◽

Cited By ~ 9

Author(s):

Yunbo Shi ◽

Wang Miao ◽

Junfang Teng ◽

Lingli Zhang

Keyword(s):

Neuronal Apoptosis ◽

Neuronal Damage ◽

Dependent Manner ◽

Ginsenoside Rb1 ◽

Seizure Duration ◽

Neuroprotective Effects ◽

Induced Neuron ◽

Neuron Injury

Background/Aims: Ginsenoside Rb1 (Rb1) has been reported to have varieties of neuroprotective effects. This study aimed to evaluate the effects of Rb1 on pentylenetetrazol (PTZ)-induced rat brain injury and Mg2+ free-induced neuron injury and analyzed the detailed molecular mechanisms in vivo and in vitro. Methods: Seizure duration and latency were measured in epilepsy kindled rat. The cognitive impairment was assessed by Morris water maze (MWM) test. Oxidative stress parameters, malondialdehyde (MDA) and glutathione (GSH) were measured by the 2-thiobarbituric acid methods and the DTNB-GSSG reductase recycling methods. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Neuronal apoptosis was measured by Annexin V-FITC and propidium iodide (PI) staining. Immunohistochemistry and immunofluorescence staining were performed to evaluate Nrf2 and HO-1 expressions. Expression of Nrf2, HO-1, Bcl-2, iNOS and LC3 were evaluated by western blot. Results: The PTZ-injured rats presented longer seizure duration and shorter seizure latency. Rb1 ameliorated these effects, as well as the cognitive deficits caused by PTZ exposure. Besides, Rb1 dose-dependently increased GSH levels, decreased MDA levels and alleviated neuronal damage in PTZ-treated rats. In vitro, Rb1 increased cell viability and decreased neuronal apoptosis in a dose-dependent manner under Mg2+ free condition. Moreover, in vivo and in vitro, Rb1 enhanced both the Nrf2 and HO-1 expressions. Furthermore, upregulation of the expression of Bcl-2 and downregulation of the expression of iNOS and LC3 were observed. However, knockdown of Nrf2 adversely affected the protective effects of Rb1 in epileptic hippocampal neurons. Conclusion: Rb1 conferred neuroprotective effects against PTZ-induced brain damage and Mg2+ free-induced neuron injury by activating Nrf2/ARE signaling.

Download Full-text

Correlation of CGS 19755 Neuroprotection against in vitro Excitotoxicity and Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.108 ◽

1995 ◽

Vol 15 (5) ◽

pp. 865-876 ◽

Cited By ~ 23

Author(s):

Miguel A. Pérez-Pinzón ◽

Carolina M. Maier ◽

Edward J. Yoon ◽

Guo-Hua Sun ◽

Rona G. Giffard ◽

...

Keyword(s):

Neuronal Damage ◽

Focal Cerebral Ischemia ◽

Neuroprotective Effect ◽

Primary Cultures ◽

Arterial Occlusion ◽

Neuroprotective Effects ◽

Brain Levels ◽

Cgs 19755

The in vivo neuroprotective effect and brain levels of cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from fetal mice were injured by exposure to 500 μM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 μmM, and against OGD the ED50 was 15.2 μM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 μM and 5 μM, respectively, at 1 h, 6 μM and 5 μM at 2 h, and 13 μM and 7 μM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

Download Full-text

AZP2006, a new promising treatment for Alzheimer’s and related diseases

Scientific Reports ◽

10.1038/s41598-021-94708-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

N. Callizot ◽

C. Estrella ◽

S. Burlet ◽

A. Henriques ◽

C. Brantis ◽

...

Keyword(s):

Therapeutic Application ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Potential Therapeutic Application ◽

Promising Treatment ◽

Central Synapses ◽

First Time ◽

Pgrn Level

AbstractProgranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

Download Full-text

Neuroprotective Effects of the FGF21 Analogue LY2405319

Journal of Alzheimer s Disease ◽

10.3233/jad-200837 ◽

2021 ◽

pp. 1-13

Author(s):

Claire Rühlmann ◽

David Dannehl ◽

Marcus Brodtrück ◽

Andrew C. Adams ◽

Jan Stenzel ◽

...

Keyword(s):

Glial Cells ◽

Neuroprotective Effect ◽

Amyloid Β ◽

Fibroblast Growth Factor 21 ◽

Neuroprotective Effects ◽

Organotypic Brain Slice ◽

Brain Slice Cultures ◽

Abca1 Mrna

Background: To date, there are no effective treatments for Alzheimer’s disease (AD). Thus, a significant need for research of therapies remains. Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.

Download Full-text

Humanin is an endogenous activator of chaperone-mediated autophagy

The Journal of Cell Biology ◽

10.1083/jcb.201606095 ◽

2017 ◽

Vol 217 (2) ◽

pp. 635-647 ◽

Cited By ~ 33

Author(s):

Zhenwei Gong ◽

Inmaculada Tasset ◽

Antonio Diaz ◽

Jaime Anguiano ◽

Emir Tas ◽

...

Keyword(s):

Quality Control ◽

Cell Death ◽

Heat Shock Protein 90 ◽

Protective Effects ◽

Neuroprotective Effects ◽

Selective Degradation ◽

Cytosolic Side ◽

Chaperone Mediated Autophagy

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

Download Full-text