Inhibition of Oxidative Stress and Related Signaling Pathways in Neuroprotection

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 19297

Special Issue Editor

Special Issue Information

Dear Colleagues,

As the world’s population is getting older, neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, represent a growing medical, economic, and social threat. The progressive loss of neuronal cells in vulnerable brain areas is the most prominent hallmark of neurodegenerative diseases. Oxidative stress is one of the major underlying mechanisms of neuronal death. It also drives other molecular and cellular mechanisms that exacerbate the detrimental consequences of redox imbalance. These include excitotoxicity, endoplasmic reticulum stress and the disturbance of calcium homeostasis, the alteration of the brain lipid profile, and the impairment of mitochondrial function and protein aggregation, to mention the most important ones, which are followed by pronounced inflammation, gliosis, axonal degeneration, the impairment of synaptic transmission, and ultimately, neuronal death.

Oxidative stress can be the initiating factor in the activation of various redox-sensitive signalling pathways which are highly implicated in the onset and progression of molecular and cellular mechanisms driving neurodegeneration. Several transcription factors, including Nrf2, PPARγ, NF- κB and p53, are particularly important in tuning antioxidative activity, inflammatory responses and neuronal death or survival upon the disruption of redox balance. The activation of MAP kinases ERK1/2, JNK and p38, together with the activation of the Akt/PKB pathway and its downstream effector PI-3K, also plays an important role in the neuronal response to oxidative stress and neuroprotection. The contribution of lipid signalling pathways in neurodegenerative diseases is slowly beginning to be elucidated.

Unfortunately, although considerable progress has been made towards understanding the pathological mechanisms involved in neurodegeneration, this knowledge has not yet been successfully translated into clinics. Current therapeutic options are limited and bring only a temporary relief from the symptoms. As oxidative stress is highly involved in various pathological processes accompanying neurodegeneration, pharmacological strategies focused on the prevention or attenuation of oxidative injury are considered as relevant approaches in neuroprotection. Various phytochemicals, as well as other natural and synthetic compounds, capable of regaining redox homeostasis and attenuating the oxidative stress-induced modulation of intracellular signalization in injured neurons, could represent valuable research avenues in neuroprotection.

The Special Issue entitled “Inhibition of Oxidative Stress and Related Signaling Pathways in Neuroprotection” is hence devoted to gathering the latest findings covering novel neuroprotective niches in in vitro and in vivo settings that prevent or delay neuronal loss by targeting oxidative stress and related signalling pathways. Hopefully, a better understanding of cellular and molecular mechanisms of action of neuroprotective compounds along intracellular signalling cascades may pave the way toward effective therapies that are eagerly awaited.

Dr. Maja Jazvinšćak Jembrek
Guest Editor

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Keywords

  • neuroprotection
  • oxidative stress
  • signalling pathways
  • nutraceuticals
  • neuroprotective drugs
  • mitochondrial function
  • neuroinflammation
  • apoptosis
  • autophagy
  • astrocytes

Published Papers (9 papers)

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Research

Jump to: Review

15 pages, 20151 KiB  
Article
Epimedium Aqueous Extract Ameliorates Cerebral Ischemia/Reperfusion Injury through Inhibiting ROS/NLRP3-Mediated Pyroptosis
by Xiaoyu Wu, Jiajia Wei, Yang Yi, Guotao Shu, Zhixu He, Qihai Gong and Jianmei Gao
Antioxidants 2023, 12(5), 999; https://doi.org/10.3390/antiox12050999 - 25 Apr 2023
Viewed by 1455
Abstract
Cerebral ischemia/reperfusion causes exacerbated neuronal damage involving excessive neuroinflammation and oxidative stress. ROS is considered a signal molecule to activate NLRP3; thus, the ROS/NLRP3/pyroptosis axis plays a vital role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Therefore, targeting the inhibition of the [...] Read more.
Cerebral ischemia/reperfusion causes exacerbated neuronal damage involving excessive neuroinflammation and oxidative stress. ROS is considered a signal molecule to activate NLRP3; thus, the ROS/NLRP3/pyroptosis axis plays a vital role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Therefore, targeting the inhibition of the ROS/NLRP3/pyroptosis axis may be a promising therapeutic tactic for CIRI. Epimedium (EP) contains many active ingredients (ICA, ICS II, and ICT), which have a wide range of pharmacological activities. However, whether EP can protect against CIRI remains unknown. Thus, in this study, we designed to investigate the effect and possible underlying mechanism of EP on CIRI. The results showed that treatment with EP dramatically mitigated brain damage in rats following CIRI, which was achieved by suppressing mitochondrial oxidative stress and neuroinflammation. Furthermore, we identified the ROS/NLRP3/pyroptosis axis as a vital process and NLRP3 as a vital target in EP-mediated protection. Most interestingly, the main compounds of EP directly bonded with NLRP3, as reflected by molecular docking, which indicated that NLRP3 might be a promising therapeutic target for EP-elicited cerebral protection. In conclusion, our findings illustrate that ICS II protects against neuron loss and neuroinflammation after CIRI by inhibiting ROS/NLRP3-mediated pyroptosis. Full article
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19 pages, 4338 KiB  
Article
Epigallocatechin-3-Gallate Attenuates Leukocyte Infiltration in 67-kDa Laminin Receptor-Dependent and -Independent Pathways in the Rat Frontoparietal Cortex following Status Epilepticus
by Ji-Eun Kim, Duk-Shin Lee and Tae-Cheon Kang
Antioxidants 2023, 12(4), 969; https://doi.org/10.3390/antiox12040969 - 20 Apr 2023
Viewed by 1264
Abstract
Status epilepticus (SE) evokes leukocyte infiltration in the frontoparietal cortex (FPC) without the blood-brain barrier disruption. Monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) regulate leukocyte recruitments into the brain parenchyma. Epigallocatechin-3-gallate (EGCG) is an antioxidant and a ligand for non-integrin 67-kDa [...] Read more.
Status epilepticus (SE) evokes leukocyte infiltration in the frontoparietal cortex (FPC) without the blood-brain barrier disruption. Monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) regulate leukocyte recruitments into the brain parenchyma. Epigallocatechin-3-gallate (EGCG) is an antioxidant and a ligand for non-integrin 67-kDa laminin receptor (67LR). However, it is unknown whether EGCG and/or 67LR affect SE-induced leukocyte infiltrations in the FPC. In the present study, SE infiltrated myeloperoxidase (MPO)-positive neutrophils, as well as cluster of differentiation 68 (CD68)-positive monocytes in the FPC are investigated. Following SE, MCP-1 was upregulated in microglia, which was abrogated by EGCG treatment. The C–C motif chemokine receptor 2 (CCR2, MCP-1 receptor) and MIP-2 expressions were increased in astrocytes, which were attenuated by MCP-1 neutralization and EGCG treatment. SE reduced 67LR expression in astrocytes, but not endothelial cells. Under physiological conditions, 67LR neutralization did not lead to MCP-1 induction in microglia. However, it induced MIP-2 expression and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in astrocytes and leukocyte infiltration in the FPC. Co-treatment of EGCG or U0126 (an ERK1/2 inhibitor) attenuated these events induced by 67LR neutralization. These findings indicate that the EGCG may ameliorate leukocyte infiltration in the FPC by inhibiting microglial MCP-1 induction independent of 67LR, as well as 67LR-ERK1/2-MIP-2 signaling pathway in astrocytes. Full article
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17 pages, 2993 KiB  
Article
Through Its Powerful Antioxidative Properties, L-Theanine Ameliorates Vincristine-Induced Neuropathy in Rats
by Chih-Chuan Yang, Mao-Hsien Wang, Hung-Sheng Soung, Hsiang-Chien Tseng, Feng-Huei Lin, Kuo-Chi Chang and Cheng-Chia Tsai
Antioxidants 2023, 12(4), 803; https://doi.org/10.3390/antiox12040803 - 25 Mar 2023
Cited by 3 | Viewed by 2407
Abstract
L-theanine (LT), which is a major amino acid found in green tea, was shown to alleviate Vincristine (VCR)-induced peripheral neuropathy and associated neuronal functional changes in rats. To induce peripheral neuropathy, rats were administered VCR at a dose of 100 mg/kg/day intraperitoneally on [...] Read more.
L-theanine (LT), which is a major amino acid found in green tea, was shown to alleviate Vincristine (VCR)-induced peripheral neuropathy and associated neuronal functional changes in rats. To induce peripheral neuropathy, rats were administered VCR at a dose of 100 mg/kg/day intraperitoneally on days 1–5 and 8–12, while control rats received LT at doses of 30, 100, and 300 mg/kg/day intraperitoneally for 21 days or saline solution. Electrophysiological measurements were taken to evaluate the nerve functional loss and recovery through motor and sensory nerve conduction velocities. The sciatic nerve was examined for several biomarkers, including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total calcium, IL-6, IL-10, MPO, and caspase-3. The results showed that VCR caused significant hyperalgesia and allodynia in rats; decreased nerve conduction velocity; increased NO and MDA levels; and decreased GSH, SOD, CAT, and IL-10 levels. LT was found to significantly reduce VCR-induced nociceptive pain thresholds, decrease oxidative stress levels (NO, MDA), increase antioxidative strength (GSH, SOD, CAT), and reduce neuroinflammatory activity and apoptosis markers (caspase-3). LT’s antioxidant, calcium homeostasis, anti-inflammatory, anti-apoptotic, and neuroprotective properties make it a potential adjuvant to conventional treatment in VCR-induced neuropathy in rats. Full article
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19 pages, 15612 KiB  
Article
Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death
by Beom-Seok Kang, Bo-Young Choi, A-Ra Kho, Song-Hee Lee, Dae-Ki Hong, Min-Kyu Park, Si-Hyun Lee, Chang-Juhn Lee, Hyeun-Wook Yang, Seo-Young Woo, Se-Wan Park, Dong-Yeon Kim, Jae-Bong Park, Won-Suk Chung and Sang-Won Suh
Antioxidants 2023, 12(2), 491; https://doi.org/10.3390/antiox12020491 - 15 Feb 2023
Cited by 3 | Viewed by 1913
Abstract
Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that [...] Read more.
Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke. Full article
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17 pages, 6513 KiB  
Article
Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats
by Ji-Eun Kim, Hana Park and Tae-Cheon Kang
Antioxidants 2023, 12(1), 156; https://doi.org/10.3390/antiox12010156 - 09 Jan 2023
Cited by 3 | Viewed by 1269
Abstract
Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic [...] Read more.
Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus. Full article
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35 pages, 7743 KiB  
Article
Neuroprotective Capability of Narcissoside in 6-OHDA-Exposed Parkinson’s Disease Models through Enhancing the MiR200a/Nrf-2/GSH Axis and Mediating MAPK/Akt Associated Signaling Pathway
by Ru-Huei Fu, Chia-Wen Tsai, Shih-Ping Liu, Shao-Chih Chiu, Yen-Chuan Chen, Yu-Ting Chiang, Yun-Hua Kuo, Woei-Cherng Shyu and Shinn-Zong Lin
Antioxidants 2022, 11(11), 2089; https://doi.org/10.3390/antiox11112089 - 23 Oct 2022
Cited by 8 | Viewed by 2239
Abstract
We assessed the antioxidant potential of narcissoside from Sambucus nigra flowers (elderflowers) in Parkinson’s disease models in vitro and in vivo. The results showed that narcissoside lessened the 6-hydroxydopamine (6-OHDA)-induced increase in reactive oxygen species (ROS) and apoptosis in SH-SY5Y cells. In the [...] Read more.
We assessed the antioxidant potential of narcissoside from Sambucus nigra flowers (elderflowers) in Parkinson’s disease models in vitro and in vivo. The results showed that narcissoside lessened the 6-hydroxydopamine (6-OHDA)-induced increase in reactive oxygen species (ROS) and apoptosis in SH-SY5Y cells. In the 6-OHDA-exposed Caenorhabditis elegans model, narcissoside reduced degeneration of dopaminergic neurons and ROS generation, and also improved dopamine-related food-sensitive behavior and shortened lifespan. Moreover, NCS increased total glutathione (GSH) by increasing the expression of the catalytic subunit and modifier subunit of γ-glutamylcysteine ligase in cells and nematodes. Treatment with a GSH inhibitor partially abolished the anti-apoptotic ability of narcissoside. Furthermore, narcissoside diminished the 6-OHDA-induced phosphorylation of JNK and p38, while rising activities of ERK and Akt in resisting apoptosis. The antioxidant response element (ARE)-luciferase reporter activity analysis and electromobility gel shift assay showed that narcissoside promotes the transcriptional activity mediated by Nrf2. Finally, we found that narcissoside augmented the expression of miR200a, a translational inhibitor of the Nrf2 repressor protein Keap1. Downregulation of Nrf2 and miR200a by RNAi and anti-miR200a, respectively, reversed the neuroprotective ability of narcissoside. In summary, narcissoside can enhance the miR200a/Nrf2/GSH antioxidant pathway, alleviate 6-OHDA-induced apoptosis, and has the neuroprotective potential. Full article
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21 pages, 5315 KiB  
Article
Omarigliptin Mitigates 6-Hydroxydopamine- or Rotenone-Induced Oxidative Toxicity in PC12 Cells by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Actions
by Noha A. Gouda and Jungsook Cho
Antioxidants 2022, 11(10), 1940; https://doi.org/10.3390/antiox11101940 - 28 Sep 2022
Cited by 5 | Viewed by 1748
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to exhibit promising effects on several pathological processes associated with Parkinson’s disease (PD). To explore its repositioning potential as an antiparkinsonian agent, we evaluated the effects of omarigliptin (OMG), a DPP-4 inhibitor recently approved as a hypoglycemic [...] Read more.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to exhibit promising effects on several pathological processes associated with Parkinson’s disease (PD). To explore its repositioning potential as an antiparkinsonian agent, we evaluated the effects of omarigliptin (OMG), a DPP-4 inhibitor recently approved as a hypoglycemic drug, on neurotoxin-induced toxicity, using PC12 cells as a cellular model of PD. The molecular mechanism(s) underlying its protective activity was also investigated. OMG alleviated oxidative toxicity and the production of reactive oxygen species induced by 6-hydroxydopamine (6-OHDA) or rotenone. It also partially attenuated the formation of DPPH radicals and lipid peroxidation, demonstrating the antioxidant properties of OMG. OMG upregulated Nrf2 and heme oxygenase-1 (HO-1). Notably, treatment with a selective HO-1 inhibitor and Nrf2 knockdown by siRNA abolished the beneficial effects of OMG, indicating that the activated Nrf2/HO-1 signaling was responsible for the protective activity. Moreover, OMG exhibited anti-inflammatory activity, blocking inflammatory molecules, such as nitric oxide (NO) and inducible NO synthase, through inhibition of IκBα phosphorylation and NF-κB activation in an Akt-dependent fashion. Finally, OMG decreased the levels of cleaved caspase-3 and Bax and increased the level of Bcl-2, indicating its anti-apoptotic properties. Collectively, these results demonstrate that OMG alleviates the neurotoxin-induced oxidative toxicity through Nrf2/HO-1-mediated antioxidant, NF-κB-mediated anti-inflammatory, and anti-apoptotic mechanisms in PC12 cells. Our findings elucidating multiple mechanisms of antiparkinsonian activity strongly support the therapeutic potential of OMG in the treatment of PD. Full article
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15 pages, 2896 KiB  
Article
Neurolocomotor Behavior and Oxidative Stress Markers of Thiazole and Thiazolidinedione Derivatives against Nauphoeta cinerea
by Pedro Silvino Pereira, Adrielle Rodrigues Costa, Thalyta Julyanne Silva de Oliveira, Carlos Vinícius Barros Oliveira, Maria do Carmo Alves de Lima, Jamerson Ferreira de Oliveira, Bonglee Kim, Henrique D. M. Coutinho, Antonia Eliene Duarte, Jean Paul Kamdem and Teresinha Gonçalves da Silva
Antioxidants 2022, 11(2), 420; https://doi.org/10.3390/antiox11020420 - 18 Feb 2022
Cited by 3 | Viewed by 1807
Abstract
Thiazolidine compounds NJ20 {(E)-2-(2-(5-bromo-2-methoxybenzylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole} and NW05 [(2-(benzo (d) (1,3) dioxol-4-ylmethylene)-N-(4-bromophenyl)-thiosemicarbazone] potentiated the effect of norfloxacin in resistant bacteria; however, there are no reports on their effects on Nauphoeta cinerea in the literature. The objective of this work was to evaluate the behavioral effects [...] Read more.
Thiazolidine compounds NJ20 {(E)-2-(2-(5-bromo-2-methoxybenzylidene)hydrazinyl)-4-(4-nitrophenyl)thiazole} and NW05 [(2-(benzo (d) (1,3) dioxol-4-ylmethylene)-N-(4-bromophenyl)-thiosemicarbazone] potentiated the effect of norfloxacin in resistant bacteria; however, there are no reports on their effects on Nauphoeta cinerea in the literature. The objective of this work was to evaluate the behavioral effects and oxidative markers of NW05 and NJ20 in lobster cockroach N. cinerea. To evaluate the behavioral study, a video tracking software was used to evaluate the locomotor points and the exploratory profile of cockroaches in the horizontal and vertical regions of a new environment. The total concentration of thiol and reduced glutathione (GSH), substances reactive to thiobarbituric acid (TBARS), free iron (II) content and mitochondrial viability were determined. The antioxidant potential was evaluated by the DPPH method. Both substances induced changes in the behavior of cockroaches, showing a significant reduction in the total distance covered and in the speed. In the cell viability test (MTT), there was a significant reduction for NJ20 (1 mM). NJ20 caused a significant increase in total levels of thiol and non-protein thiol (NPSH), although it also slightly increased the content of malondialdehyde (MDA). Both compounds (NW05 and NJ20) caused a significant reduction in the content of free iron at a concentration of 10 mM. In conclusion, the compound NJ20 caused moderate neurotoxicity (1 mM), but had good antioxidant action, while NW05 did not show toxicity or significant antioxidant activity in the model organism tested. It is desirable to carry out complementary tests related to the antioxidant prospection of these same compounds, evaluating them at different concentrations. Full article
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Review

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36 pages, 849 KiB  
Review
Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions
by Ana Tadijan, Ignacija Vlašić, Josipa Vlainić, Domagoj Đikić, Nada Oršolić and Maja Jazvinšćak Jembrek
Antioxidants 2022, 11(10), 2049; https://doi.org/10.3390/antiox11102049 - 18 Oct 2022
Cited by 15 | Viewed by 3990
Abstract
In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors [...] Read more.
In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion. Cannabinoids are able to neutralize free radicals and modulate the production of reactive oxygen species and the activity of antioxidative systems acting on CB1 and CB2 cannabinoid receptors. The activation of CB1 receptors stimulates signaling pathways involved in antioxidative defense and survival (such as the phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and Nrf2 pathways) and regulates glutamatergic signaling, the activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx, and the induction of Ca2+-regulated signaling cascades, whereas the neuroprotective effects mediated by CB2 receptors are due to the suppression of microglial activation and the release of prooxidative and proinflammatory mediators. This review summarizes the main molecular mechanisms and new advances in understanding the antioxidative and neuroprotective effects of cannabinoids. Because of the plethora of possible pharmacological interventions related to oxidative stress and cannabinoid-mediated neuroprotection, future research should be directed towards a better understanding of the interplay between activated signal transduction pathways and molecular targets with the aim to improve treatment options and efficacy by targeting the endocannabinoid system. Full article
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