**5. Phytochemicals that activate neuronal antioxidant defense and survival mediating against lipid peroxidation**

Many plant-derived bioactive molecules deactivate ROS and reportedly, potentiating the cellular antioxidant system. The principle of action of inducing an antioxidant effect by promoting adaptive cellular stress response using phytochemicals is substantially supported [110]. Furthermore, phytochemicals have been shown to protect neurons from OS by activating TrkB signaling pathways and the Nrf2-ARE system promoting cellular survival [77, 78].

## **5.1 Phenolic compounds and OS in brain neurological damages**

### *5.1.1 Sulfuretin quenches oxidative stress effects*

Numerous phenolics exhibit neuroprotective effects against OS in models of AD and other neurodegenerative disorders. Sulfuretin (**Figure 2**), a flavonoid glycoside isolated from the stem bark of *Albizia julibrissin* and heartwood of *Rhus verniciflua*, protected SH-SY5Y cells and primary hippocampal neurons from Aβ-induced neurotoxicity [111]. The PI3K/Akt and Nrf2/HO-1 signaling pathways may contribute to sulfuretin-mediated neuroprotection through inhibiting cell death by suppressing ROS production, enhancing PI3K/Akt pathway and the nuclear translocation of Nrf2 (**Figure 3**) [62]. Also, the phytochemical sulfuretin was shown to suppress adipocyte differentiation of preadipocytes and prevented obesity and increased insulin sensitivity by suppressing expression of inflammatory markers, inducing expression of adiponectin, and increasing concentrations of phosphorylated ERK and AKT [112]. Using a microarray analysis and identification of activating

**Figure 2.** *Sulfuretin.* *Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

#### **Figure 3.**

*Other inhibitory effects of sulfuretin. ERK- extracellular signal-regulated kinase; AKT- protein kinase B (PKB); GSK3*β*- glycogen synthase kinase 3 beta; PARP = poly (adenosine diphosphate-ribose) polymerase; MPP+ - 1-methyl-4-phenylpyridinium. inhibition; increases; decreases. MPP+ arises as the toxic metabolite of the compound MPTP. MPTP is converted in the brain into MPP+ causing parkinsonism killing dopamine-producing neurons in the substantia nigra through oxidative stress generation which is inhibited by sulfretin.*

transcription factor 3 (Atf3) as a sulfuretin-responsive gene, the molecular mechanism of sulfuretin in adipocytes was illuminated. Administration of sulfuretin raised the Atf3 mRNA and protein concentrations in white adipose tissue and adipocytes. Reliably, Atf3 deficiency promoted lipid accretion, the adipocyte expression and lipid peroxidation markers. Sulfuretin's but not resveratrol's antiadipogenic effects were diminished in cell with Atf3 deficiency, indicating that Atf3 is an essential factor in the function of sulfuretin [112] and that phytochemicals are essential for as antioxidant agents.

#### *5.1.2 Resveratrol has antioxidant effects in brain disease*

By activating the PI3K/Akt/Nrf2 pathway, the grape polyphenol and anthocyanin, Resveratrol (**Figure 4**), and a derivative of Korean black beans, protected PC12 cells [81] and HT22 cells [113], respectively, against Aβ-induced toxicity. In Aβ-induced toxicity, resveratrol inhibited cell death and suppressed OS markers such as MDA and ROS by elevation of the phosphorylation of PI3K and Akt, the nuclear translocation of Nrf2, and the protein concentrations of SOD, HO-1, and GSH [81]. Anthocyanins diminished cell death by modifying the expressions of proapoptotic markers (cleaved caspase-3) and stress markers (MDA, H2O2, 8-OHdG) while enhancing the glycogen synthase kinase-3 beta (GSK3b), phosphorylation of PI3K and Akt, the nuclear translocation of Nrf2, the expression of HO-1, and GSH levels.

#### **Figure 4.**

*Resveratrol whose chemical name is 3,5,4′-trihydroxy-trans-stilbene is a stilbenoid, a type of natural polyphenol, and a phytoalexin synthesized by numerous plants in response to injury or when the plant is under attack by pathogens, such as (viruses, bacteria or fungi).*

#### *5.1.3 Tea polyphenols, oxidative stress, neuroprotection*

Tea polyphenols (TPs) attenuated OS in H2O2-stimulated SH-SY5Y cells by activating the Keap1-Nrf2 signaling pathway and the TrkB/CREB/BDNF pathway [114]. Also in these experiments, TPs attenuated H2O2-induced cell death, mitochondrial dysfunction and reduced elevated ROS and H2O2 concentrations. Moreover, TPs heightened the nuclear translocation of Nrf2 and the TrkB/CREB/BDNF signaling mechanism by activating the PI3K/Akt pathway, and thus, transcriptionally regulating the downstream expressions of HO-1, NQO1, SOD, GPx, and CAT in SH-SY5Y cells [114].

#### *5.1.4 Isoflavone of fermented soy and neuroprotection*

8-Hydroxydaidzein (8-OHD), an isoflavone of fermented soy, protected against neuroinflammation in LPS-stimulated BV2 microglial cells by stimulating Nrf2 antioxidant and Akt/NF-kB inflammatory signaling pathways. In BV2 microglial cells, 8-OHD inhibited the LPS-activated productions of NO, TNF-a, and IL-6 by suppressing gene expression [115]. Moreover, 8-OHD quenches ROS and promotes the nuclear translocation of Nrf2, and thus, upregulates the expressions of Phase II enzymes, such as HO-1, NQO1, and GCL [115]. 8-OHD also suppresses the LPS-stimulated phosphorylation of Akt and NF-kB-p65 attenuating LPS-induced prostaglandin E2 (PGE2) production without affecting COX-2 expression [116].

#### *5.1.5 Rutin protection against neurotoxicity*

A flavonoid found in buckwheat, rutin protected male albino SD rats from acrylamide or g-radiation-induced neurotoxicity by activating the PI3K/Akt/ GSK-3b/NRF-2 signaling pathway (**Figure 5**) [118]. Rutin (**Figure 5**) increases the phosphorylation of PI3K, Akt, and GSK-3b and the nuclear translocation of Nrf2, suppressed MDA levels, GST activity, and the expressions of IL-1b and IL-6, and increased IGF1 and NGF levels [118]. The phytochemical rutin's mechanisms of action includes reduction of proinflammatory cytokines, increasing antioxidant enzyme activities, stimulation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the functions of mitochondrial complex enzymes [119]. Taken together, these suggest that they phytotherapeutic rutin may be a hopeful neuroprotective compound for the treatment of NDDs.

Rutin as neuroprotective agent has been seen to move from bench to the bedside as a phytotherapeutic [120] as well as the inhibition of neuroinflammation and

*Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

#### **Figure 5.**

*Rutin, also called rutoside, quercetin-3-O-rutinoside and sophorin, is the glycoside combining the flavonol quercetin and the disaccharide rutinose (*α*-L-rhamnopyranosyl-(1* → *6)-*β*-D-glucopyranose) [117].*

providing neuroprotection in subarachnoid hemorrhage through suppressing the RAGE-NF-κB inflammatory signaling pathway [121].

Rutin has anti-inflammatory, antioxidant, anti-viral, anti-tumor and immune regulatory effects. Neuroprotective mechanisms of rutin for spinal cord injury has been reported to occur through anti-oxidation and anti-inflammation and inhibition of p38 mitogen activated protein kinase pathway [122].

#### **5.2 Non-phenolic compounds, neuroprotection and lipid peroxidation**

Numerous non-phenolics have been reported to exhibit neuroprotective effects against OS in models of AD and other neurodegenerative disorders [62].

#### *5.2.1 Brassicaphenanthrene A, acerogenin A and neuroprotection*

Isolated from *Brassica rapa*, Brassicaphenanthrene A protects HT-22 neuronal cells from glutamate-induced excitotoxicity and upregulates Nrf2-mediated HO-1 expression via PI3K/Akt and JNK regulatory pathways [123]. Acerogenin A, an isolate from the stem bark of Acer *nikoense* (Japanese traditional medicine) protected HT22 cells from glutamate-induced oxidative injury [124] through the stimulating the PI3K/Akt/Nrf2/HO-1 pathway. Acerogenin A diminished cell death by suppressing the production of ROS and increasing the nuclear translocation of Nrf2, the expression of HO-1, and the phosphorylation of Akt [124].

**Polysaccharide extracts** (PPE) of *Perilla frutescens* triggered PI3K/Akt and Nrf2-mediated HO-1/NQO1 pathways and protected against H2O2-induced OS in HT22 cells [125]. The PPE attenuates cell damage by suppressing the expressions of Bax, cytochrome C, and caspases-3,-8, and − 9, and enhancing the expressions Bcl-2 and Poly [ADP-ribose] polymerase (PARP) while increasing MAPKs (p38, ERK, JNK), PI3K, Akt and p65 phosphorylation, decreasing NF-kB concentration and enhancing the nuclear translocation of Nrf2 and the expressions of HO-1 and SOD [125].

**3,3'-Diindolylmethane,** a metabolite of indole-3-carbinol found in Brassicaceae family, attenuates OS in glutamate-induced HT-22 cells by activation of the TrkB/ Akt pathway [126]. 3,3'-Diindolylmethane metabolite moderates the expressions

of Bax, cytochrome c, cleaves caspase-3, and AIF (apoptosis-inducing factor), and improves Bcl-2 expression, the phosphorylation of TrkB, Akt, and CREB, and the expressions of HO-1, GCLC, NQO-1, and GPx. Scopolamine-treated mice improved cognitive deficits after 3,3'-Diindolylmethane administration [126].

**Diallyl trisulfide**, an organosulfur compound in garlic oil, stimulated the PI3K/ Akt-mediated Nrf2/HO-1 signaling pathway and protected against OGD-induced neuronal injury [127]. Also, diallyl trisulfide inhibited the expressions of proapoptotic markers (cleaved caspase-3), OS markers (ROS and MDA), and increased the nuclear translocation of Nrf2, the expression of antioxidant enzymes (e.g., HO-1), and the phosphorylation of Akt [127] thus reducing lipid peroxidation potentials in brain injury.

**Oxymatrine**, isolated from the Chinese herb *Sophora flavescens* protected P7 SD rats from hypoxic–ischemic brain injury [128], through activating the Akt/ GSK3b/HO-1/Nrf-2 signaling pathway. Moreover, oxymatrine increased the nuclear translocation of Nrf2, the phosphorylation of Akt and GSK3b, and HO-1 expression and attenuated the degree of neurological deficits [128].

**6'-O-Galloylpaeoniflorin**, a galloylated derivative of paeoniflorin isolated from peony root, protected an OGD-induced ischemic PC12 cell model and a CIRI male Wistar rat model against ischemic stroke through stimulating PI3K/Akt/Nrf2 pathway [129]. Also, 6'-O-galloylpaeoniflorin attenuated OS and neuroinflammation while improving neurological deficits, inhibiting apoptosis by suppressing the expressions of pro-apoptotic markers (cleaving caspase-3), inhibiting inflammatory cytokine (TNF-a, IL-1b), and MDA concentration. Nuclear translocation of Nrf2 and SOD expression increased through elevation of Akt phosphorylation [129].

**Ginkgolides A, B and C** are diterpenes isolated from *Ginkgo biloba* L. and defends PC12 cells from OGD/R-induced ischemic injury in adult male SD rats subjected to MCAO-induced acute cerebral ischemic injury [130]. They stimulate Akt/Nrf2 and Akt/CREB signaling pathways. These ginkgolides inhibit cell death by overwhelming the expressions of Bax and cleaved caspase-3, enhancing the phosphorylation of Akt and pCREB, and increasing the nuclear translocation of Nrf2 and HO-1 expression [130]. Also, ginkgolides protects against ischemic stroke in an OGD-induced SH-SY5Y cell ischemic model and MCAO-induced model of cerebral ischemic injury in male SD rats [131]. Ginkgolides suppress ROS production and increase Akt phosphorylation, the nuclear translocation and phosphorylation of Nrf2, and the expressions of HO-1, Nqo1, and SOD [131]. In the process lipid peroxidation associated damages are averted.

PC12 cells are protected against OGD/R-induced neuronal injury by **Protodioscin** which actuates the PI3K/Akt/Nrf2 pathway. This occurs through elevating the expressions of HIF-1a, SOD, GPx, HSP70, and HO-1, the phosphorylation of PI3K and Akt, the nuclear translocation of Nrf2, and upregulating miR-124. As a result, OS is attenuated [132] and lipid peroxidation reduced.

**Matrine,** a quinolizidine alkaloid, derived from the herb Radix Sophorae *flavescentis*, protected rats from subarachnoid hemorrhage [133] through PI3K/Aktmediated NF-kB inhibition and Keap1/Nrf2-dependent HO-1 induction. The effects of matrine included inflammatory cytokines (TNF-a, IL-1b) and pro-apoptotic markers (Bax and cleaved caspase-3) expression suppression with enhanced prosurvival marker Bcl-2 ([133]. Also, matrine increased nuclear translocation of Nrf2 and HO-1 expression and lowered NF-kB P65 expression by increasing the phosphorylation of Keap1, Akt, and IkB-a [72] invariably attenuating lipid peroxidation.

**Panax notoginseng saponins** protected against blood–brain barrier (BBB) injury [134] by activating the PI3K/Akt/Nrf2 antioxidant signaling pathway. In LPS-stimulated cerebral microvascular endothelial cells BBB injury model,

*Phytotherapeutics Attenuation of Oxidative Stress, Inflammation and Lipid Peroxidation… DOI: http://dx.doi.org/10.5772/intechopen.99832*

saponins attenuated the creations of ROS and inflammatory cytokines (ILβ1b, TNFα), decreased NFβkB levels, and increased the nuclear translocation of Nrf2 HO-1 expression, and the phosphorylation of Akt [134].
