**2.3 Antioxidant activities**

The most established bioactivity of vitamin E is its antioxidant property, primarily against lipid peroxidation in biological membranes [2]. By quenching the lipid radicals, vitamin E, as chain-breaking antioxidant, terminates the chain reaction of the oxidation of polyunsaturated fatty acids (PUFAs) [3]. This function is critical to ensure the integrity of cellular membranes and systems which rely on the abundance of PUFAs, such as the nervous system. Hence, neurological symptoms such as progressive ataxia and hyporeflexia are manifestations of vitamin E deficiency as a result of malabsorption.

Tocopherols and tocotrienols are potent antioxidants that scavenge lipid peroxyl radicals by donating hydrogen from the phenolic group on the chromanol ring [4]. A synergistic antioxidant system made up of vitamin C and other hydrogen donors such as thiol antioxidants, namely, glutathione and lipoic acid, reacts with the resulting tocotrienoxyl or tocopheroxyl radicals to regenerate vitamin E [37], returning it to its reduced state for further use (**Figure 3**). There is very little evidence in vivo for more advanced vitamin E oxidation products [34].

Packer and colleagues noted that the substituents on the chromanol nucleus and properties of side chain (saturated vs. unsaturated) were critical to the effectiveness of the different vitamin E homologs [37]. Preferential distribution of α-tocopherol to the tissues in vivo may have contributed to its greater impact compared with other homologs, but the structural differences between α-tocopherol and α-tocotrienol have given rise to differences in reactivity observed in in vitro and in vivo studies.

#### **Figure 3.**

*The antioxidant network showing the interaction among vitamin E, vitamin C, and thiol redox cycles [37]. Notes: \*thiol transferase (glutaredoxin), protein disulfide isomerase, glutathione (GSH)-dependent dehydroascorbate reductase, thioredoxin (TRX) reductase.*

**191**

**Figure 4.**

*cyclooxygenase.*

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

biochemical pathways resulting in physiologically beneficial effects.

metabolism and neurodegeneration [39] (**Figure 4**).

Tocotrienols were suggested to be more effective scavengers of peroxyl radicals due to more even distribution in the phospholipid bilayer, more effective interaction with lipid peroxyl radicals [4], stronger disordering of membrane lipids, and greater recycling of chromanoxyl radical due to closer location to the membrane surface [37]. The chromanoxyl radical of α-tocotrienol was found to be recycled in membranes and lipoproteins more quickly than the corresponding α-tocopheroxyl

The antioxidant activity of vitamin E is critical to a healthy nervous system, as evident from the consequences of neurological function under deficient condition. The vitamin E protection of PUFAs leads to neuroprotective effects under pathologic and high oxidative stress conditions. Due to the early discovery of α-tocopherol as an essential vitamer and its ubiquitous nature, most research in vitamin E, concerning the mechanisms of action and physiological implications of deficiency, has centered on tocopherols. Tocotrienols, without having any apparent consequence of deficiency and being not inherently detectable in non-supplemented humans or animals, were not the focus of vitamin E-related research until much later. Since the discovery of rich sources of tocotrienols and subsequent availability as an active ingredient, there is growing evidence that tocotrienols have superior potency in terms of antioxidant activity and modulation of impaired

Arachidonic acid (AA), one of the most abundant PUFAs of the central nervous system, is highly susceptible to oxidative metabolism under pathologic conditions. [39]. A number of neurodegenerative conditions in the human brain are associated with disturbed PUFA metabolism of AA, including acute ischemic stroke [40]. Cleaved from the membrane phospholipid bilayer by cytosolic phospholipase A2 (cPLA2), AA is metabolized by both enzymatic and nonenzymatic pathways into neurotoxic metabolites. Palm oil-derived α-tocotrienol at nanomolar concentrations has been shown to attenuate both enzymatic and nonenzymatic mediators of AA

*The arachidonic acid (AA) cascade and potential target sites for α-tocopherols (αTOC) and α-tocotrienols (αTCT) [39]. cPLA2, cytosolic phospholipase A2; 12-LOX, 12-lipoxygenase; c-Src, proto-oncogene tyrosineprotein kinase or simply c-Src (cellular sarcoma); 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; COX,* 

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

radical [38].

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease DOI: http://dx.doi.org/10.5772/intechopen.91028*

Tocotrienols were suggested to be more effective scavengers of peroxyl radicals due to more even distribution in the phospholipid bilayer, more effective interaction with lipid peroxyl radicals [4], stronger disordering of membrane lipids, and greater recycling of chromanoxyl radical due to closer location to the membrane surface [37]. The chromanoxyl radical of α-tocotrienol was found to be recycled in membranes and lipoproteins more quickly than the corresponding α-tocopheroxyl radical [38].

The antioxidant activity of vitamin E is critical to a healthy nervous system, as evident from the consequences of neurological function under deficient condition. The vitamin E protection of PUFAs leads to neuroprotective effects under pathologic and high oxidative stress conditions. Due to the early discovery of α-tocopherol as an essential vitamer and its ubiquitous nature, most research in vitamin E, concerning the mechanisms of action and physiological implications of deficiency, has centered on tocopherols. Tocotrienols, without having any apparent consequence of deficiency and being not inherently detectable in non-supplemented humans or animals, were not the focus of vitamin E-related research until much later. Since the discovery of rich sources of tocotrienols and subsequent availability as an active ingredient, there is growing evidence that tocotrienols have superior potency in terms of antioxidant activity and modulation of impaired biochemical pathways resulting in physiologically beneficial effects.

Arachidonic acid (AA), one of the most abundant PUFAs of the central nervous system, is highly susceptible to oxidative metabolism under pathologic conditions. [39]. A number of neurodegenerative conditions in the human brain are associated with disturbed PUFA metabolism of AA, including acute ischemic stroke [40]. Cleaved from the membrane phospholipid bilayer by cytosolic phospholipase A2 (cPLA2), AA is metabolized by both enzymatic and nonenzymatic pathways into neurotoxic metabolites. Palm oil-derived α-tocotrienol at nanomolar concentrations has been shown to attenuate both enzymatic and nonenzymatic mediators of AA metabolism and neurodegeneration [39] (**Figure 4**).

#### **Figure 4.**

*Neuroprotection - New Approaches and Prospects*

E in humans.

in vivo studies.

**2.3 Antioxidant activities**

deficiency as a result of malabsorption.

potentiated by eating. However, the authors recognized the conclusion derived from the study has several limitations, including small sample size, lack of randomization or blinding, and compliance issues, leading to an imbalance with attendant potential for baseline and residual confounding. Nevertheless, if proven in a larger trial, this observation changes the conventional thinking that vitamin E needs to be taken with or immediately after meal to enhance absorption and also reflects that there is still much to learn on the absorption and transport of vitamin

The most established bioactivity of vitamin E is its antioxidant property, primarily against lipid peroxidation in biological membranes [2]. By quenching the lipid radicals, vitamin E, as chain-breaking antioxidant, terminates the chain reaction of the oxidation of polyunsaturated fatty acids (PUFAs) [3]. This function is critical to ensure the integrity of cellular membranes and systems which rely on the abundance of PUFAs, such as the nervous system. Hence, neurological symptoms such as progressive ataxia and hyporeflexia are manifestations of vitamin E

Tocopherols and tocotrienols are potent antioxidants that scavenge lipid peroxyl

Packer and colleagues noted that the substituents on the chromanol nucleus and properties of side chain (saturated vs. unsaturated) were critical to the effectiveness of the different vitamin E homologs [37]. Preferential distribution of α-tocopherol

radicals by donating hydrogen from the phenolic group on the chromanol ring [4]. A synergistic antioxidant system made up of vitamin C and other hydrogen donors such as thiol antioxidants, namely, glutathione and lipoic acid, reacts with the resulting tocotrienoxyl or tocopheroxyl radicals to regenerate vitamin E [37], returning it to its reduced state for further use (**Figure 3**). There is very little evidence in vivo for more advanced vitamin E oxidation products [34].

to the tissues in vivo may have contributed to its greater impact compared with other homologs, but the structural differences between α-tocopherol and α-tocotrienol have given rise to differences in reactivity observed in in vitro and

*The antioxidant network showing the interaction among vitamin E, vitamin C, and thiol redox cycles [37]. Notes: \*thiol transferase (glutaredoxin), protein disulfide isomerase, glutathione (GSH)-dependent* 

*dehydroascorbate reductase, thioredoxin (TRX) reductase.*

**190**

**Figure 3.**

*The arachidonic acid (AA) cascade and potential target sites for α-tocopherols (αTOC) and α-tocotrienols (αTCT) [39]. cPLA2, cytosolic phospholipase A2; 12-LOX, 12-lipoxygenase; c-Src, proto-oncogene tyrosineprotein kinase or simply c-Src (cellular sarcoma); 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; COX, cyclooxygenase.*

#### **2.4 Benefits in vascular health**

Vitamin E has also been associated with improved vascular health in studies measuring arterial compliance and endothelial dysfunction as biomarkers. Vascular endothelium, which lines the blood luminal surface of vessels, is involved in the regulation of vascular tone, platelet activity, and thrombosis and intimately involved in the pathogenesis of atherosclerosis [5, 6]. The endothelium is an integral part of the vasculature and is involved in promoting an atheroprotective environment via the complementary actions of endothelial cell-derived vasoactive factors [41]. Vasomotor tone is modulated through the release of endothelium-derived relaxing factors (EDRFs) such as NO [6]. Impaired vascular homeostasis can lead to endothelial dysfunction, which contributes to atherosclerosis [41]. Intact endothelium is also needed for normal arterial compliance, a predictor of cardiovascular events. Arterial compliance, which can be assessed by pulse wave velocity (PWV) and augmentation index (AI), can be improved in healthy subjects even with dietary interventions [7].

In a randomized controlled trial, subjects with the following risk factors, hypercholesterolemia (13 subjects), smokers (14 subjects), or both (15 subjects), were supplemented with placebo or vitamin E for 4 months. The authors hypothesized that long-term supplementation with vitamin E would improve endotheliumdependent relaxation in hypercholesterolemic patients and/or chronic smoking, two risk factors that have been associated with increased radical formation, impaired endothelial vasodilator function, and increased plasma levels of autoantibodies against oxidized LDL [6]. The study found the most severe endothelial vasodilator dysfunction in patients with both risk factors present. Vitamin E significantly improved endothelium-dependent relaxation in forearm resistance vessels of hypercholesterolemic smokers. There was a significant relationship between improvement in acetylcholine-induced vasodilation and the change in autoantibody titer against oxidized LDL (*r* = −0.59; *p* = 0.002) [6].

Moreover, in a randomized controlled trial, 36 healthy male volunteers were supplemented with placebo or tocotrienol-rich vitamin (50, 100, 200 mg/day) with self-emulsifying formula for 2 months [7]. Arterial compliance was assessed using carotid-femoral PWV and AI, at baseline and after 2 months of supplementation. Subjects treated with tocotrienols at doses of 100 and 200 mg/day showed significant improvement in arterial compliance with PWV reductions of 0.77 m/s (*p* = 0.007) and 0.65 m/s (*p* = 0.002), respectively. The placebo group did not show a reduction in PWV and AI compared with baseline. The treatment had no effect on blood pressure, serum total cholesterol, and LDL-C [7], which are potential confounding factors to the observed improvement in arterial compliance. The improvement in vascular function can be achieved through mechanisms involving enhanced NO production by the endothelium and inhibition of free radicals that inactivate EDRF. Vitamin E can potentially increase the production of NO, which relaxes the vascular smooth muscle cells, while also neutralizing free radicals which preserve the action of EDRF to maintain arterial compliance [7].

In addition to promoting vascular health, vitamin E is also postulated to exert anti-atherogenic effects via its ability to decrease LDL oxidation, quench free radicals, inhibit protein kinase C (PKC), inhibit expression of adhesion molecules and monocyte transmigration, and impair vascular smooth muscle cell proliferation [8].

#### **3. Cerebral small vessel disease**

The general ischemia implicated in CSVD of small blood vessels (i.e., arterial tree occlusion in particular) involving the subcortical and deeper parts of the brain

**193**

*Neuroprotective Potentials of Natural Vitamin E for Cerebral Small Vessel Disease*

accounts for nearly 30% of all stroke subtypes worldwide [9–12].

has been widely reported to cause cerebral ischemic stroke or lacunar stroke and

The complexity and overlapping pathophysiological mechanism of the disease make the interpretation of CSVD debatable. However, it is a widely accepted view that pathological consequences of small vessel disease (SVD) on the brain parenchyma rather than the underlying diseases of the vessels serve as the basis of CSVD [13]. Hence, the injury in the brain parenchyma that is linked with leptomeningeal and intracerebral vessel pathology that vascularizes with poor collaterals in the deep white matter and subcortical gray matter is the main diagnostic landmark of CSVD. Moreover, CSVD is generally due to several vasculo-pathological processes that affect and cause occlusion to the small perforating cerebral arterioles, capillaries, and venules (of sizes 50–400 mm), which are small arteries (chiefly of middle cerebral artery tributaries) that penetrate and supply the brain subcortical region,

Several manifestations of CSVD can be seen through clinical, radiological (i.e., neuroimaging such as CT or MRI), or pathological phenomena with various etiologies [46–49]. Recent advancement in neuroimaging techniques had enabled the imaging-based (such as MRI) identification and characterization of multiple manifestation of CSVD including white matter hyperintensities (WMHs) of presumed vascular origin or leukoaraiosis, lacunes of presumed vascular origin (i.e., small subcortical infarcts and silent brain infarcts, SBI), perivascular spaces, microinfarcts, and cerebral microbleeds (CMBs) [46, 50, 51]. Alarmingly, the aforementioned lesions can be silent, and the affected individual may not have any clinical symptoms. More importantly, this silent lesion with higher number of single or multiple, is associated with higher risk of mild cognitive impairment,

There are several etiopathogenic classifications of CSVD. However, the most prevalent forms of CSVD are amyloidal CSVD (sporadic and hereditary cerebral amyloid angiopathy [CAA]) and non-amyloidal CSVD (arteriolosclerosis, agerelated, vascular risk-factor-related SVD, i.e., microatheroma, lipohyalinosis, fibrinoid necrosis, and segmental arterial disorganization) [42, 52, 53]. Other less common forms of CSVD include inherited or genetic CSVD that is recognizably different from CAA (i.e., Fabry's disease and cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy [CADASIL]), inflammatory and immunologically mediated CSVD (i.e., rheumatoid vasculitis, lupus erythematosus, and CNS vasculitis secondary to infection), venous collagenosis, and other CSVD (i.e., non-amyloid microvessel degeneration in AD and

Different manifestations of CSVD based on neuroimaging findings result in different and overlapping health burden and epidemiology [54]. Increasing age has been reported to elevate the finding of WMHs, lacunes, perivascular spaces, and CMBs in healthy populations [54–56]. However, increased vascular risk factors are consistent with the prevalence of CMBs but not in other imaging findings [56, 57]. Race, ethnicity, and gender with adjusted age also explain the variability of these imaging findings, whereby some findings had reported that higher WMH grade and volume were found in ethnic or racial minorities than non-Hispanic white [58] and WMHs were much higher in women than men, although no definite mechanism

*DOI: http://dx.doi.org/10.5772/intechopen.91028*

**3.1 Characteristic and classification**

resulting in various lesions in the brain [42–46].

postradiation angiopathy) [42, 52, 53].

**3.2 Neuroepidemiology and health burden**

dementia, Alzheimer's disease, and full-blown stroke [14, 15].

has been widely reported to cause cerebral ischemic stroke or lacunar stroke and accounts for nearly 30% of all stroke subtypes worldwide [9–12].
