**4. Prospects of vitamin E for CSVD neuroprotection**

As remarked in the previous sections, increasing body of evidence indicated that oxidative stress might play a pivotal role in the largely elusive pathomechanism of CSVD and other neurodegenerative disease, including cognitive impairment. Moreover, targeting oxidative stress, as a therapeutic approach of vascular-related disease, has been an area of continuing interest given its significance on the aging world population and the rising trend of noncommunicable disease burden, typically cardio-cerebrovascular disorders which include CSVD. However, informative and converging data on vitamin E and its neuroprotective potential for CSVD are scarce.

Central to this proposition of vitamin E potential in CSVD is the involvement of ROS in the physiological role for normal regulation of cerebral vascular event. Hence, a balance between mitigating oxidative stress and normal physiological role should be considered in this ROS-centric approach for natural vitamin E in CSVD neuroprotective potentials. Nonetheless, the idea of attaining or sustaining certain levels of antioxidants to mitigate vascular oxidative stress remains a contentious issue. For instance, antioxidants such as vitamin E have been proven beneficial for vascular function in small clinical and experimental trials [108],

*Neuroprotection - New Approaches and Prospects*

**196**

**Figure 5.**

There are multiple oxidative markers used to correlate with neurodegenerative disease including CSVD, for example, thioredoxins (positively correlate with severity of acute ischemic stroke and infarct volume) [94], thioredoxin reductase

*hyperintensities; CMBs, cerebral microbleeds; AD, Alzheimer's disease.*

*General pathomechanism and role of ROS in CSVD. ECs, endothelial cells; BBB, blood–brain barrier; ECM, extracellular matrix; cBF, cerebral blood flow; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; COX, cyclooxygenase; NADPH, nicotinamide adenine dinucleotide phosphate; MPs, microparticles; TNF-alpha, tumor necrosis factor-alpha; WMHs, white matter* 

whereby vitamin E supplementation had been shown to reduce the onset of WMHs in small clinical trials [109]. Moreover, natural vitamin E also had been shown favorable to lessen cognitive impairments in CSVD animal models

#### **Figure 6.**

*Putative neuroprotective potentials of natural vitamin E in targeting ROS in CSVD manifestations. αTCT, α-tocotrienols; αTOC, α-tocopherols; ECs, endothelial cells; BBB, blood–brain barrier; ECM, extracellular matrix; cBF, cerebral blood flow; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; COX, cyclooxygenase; NADPH, nicotinamide adenine dinucleotide phosphate; MPs, microparticles; TNF-alpha, tumor necrosis factor-alpha; WMHs, white matter hyperintensities; CMBs, cerebral microbleeds; AD, Alzheimer's disease.*

**199**

**6. Conclusion**

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

[110, 111]. Notwithstanding, a larger-scale clinical trial had shown less convincing beneficial outcomes on stroke and vascular disease prevention with antioxi-

to have potential neuroprotective effects in treating oxidative stress-induced metabolic syndrome with CSVD-related deterioration with reduced plasma level of coenzyme Q10 in experimental animal model with metabolic syndrome [82]. Nonetheless, recent studies on oxidative stress-induced diet reported weak or no apparent association in modifying the cardiovascular risk in an animal model (normotensive wild-type mice, C57BL/6 J), at least in its impact on systemic blood

Moreover, utilizing other antioxidants such as coenzyme Q10 has been reported

The inconsistency in the reports of the potential neuroprotective effects of antioxidant (natural vitamin E) in cerebrovascular disease is partly due to the apparent lack of optimization in terms of concentrations/doses of the vitamin E used. This is despite the supportive data on supra(optimal)-physiological concentration of vitamin E (especially α-tocotrienol) that can interrupt the superoxide and NO reaction [108] to reduce the activation of ROS and endpoint BBB disintegration in CSVD. Hence, we are tempted to posit that appropriate nutritive consumptions of vitamin E could prove advantageous to attenuate BBB damages that underlie CSVD heterogenous manifestations, i.e., by halting the leukocyte-EC adhesion that can further degrade the BBB damages with WMHs. Biomarkers of oxidative stress can serve to monitor the redox imbalance in individuals with WMHs while exploring the putative therapeutic avenue with targeted dietary supplements as neuroprotective potentials against CSVD onset and/or disease manifestations. As such, the vitamin E neuroprotective merits could prevent a comprising reduction of cBF in cerebral ischemia in numerous CSVD manifestations, be it silent or symptomatic,

Although data on therapeutic regimes had shown promising increased plasma levels of antioxidants, whether this translates to increased levels in the vasculature remains unknown. Even if sufficient levels of antioxidants were achieved in vascular cells, the antioxidants might in fact exert prooxidant effects as a result of their conversion to radical species following their reactions with superoxide [114, 115]. Either way, a single approach of conventional antioxidant supplementation would

Corroboratively, with multiple studies having successfully linked the potential therapeutic and neuroprotective potentials of vitamin E in vascular health domains, a multicenter and adequately powered clinical trial is much needed for CSVD. Such data would further strengthen the nutritive value of vitamin E for CSVD neuroprotective supplements. In addition, opportunities exist to examine the connectivity of white matter tracts to exhibit vitamin E role in protection of small vessel collateral circulation as well as an increased expression of proarteriogenic (new blood vessel

CSVD, as the commonest neurological condition as we age, could benefit from the potency of vitamin E antioxidant neuroprotective potentials through oxidative stress and BBB integrity modulation. This chapter converges contemporary

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

pressure [113].

dant (i.e., vitamin E) supplementation [112].

from the ROS-centric targeting (**Figure 6**).

be suboptimal in combating oxidative stress in CSVD [108].

**5. Challenge and future direction**

formation) genes in future research.

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

[110, 111]. Notwithstanding, a larger-scale clinical trial had shown less convincing beneficial outcomes on stroke and vascular disease prevention with antioxidant (i.e., vitamin E) supplementation [112].

Moreover, utilizing other antioxidants such as coenzyme Q10 has been reported to have potential neuroprotective effects in treating oxidative stress-induced metabolic syndrome with CSVD-related deterioration with reduced plasma level of coenzyme Q10 in experimental animal model with metabolic syndrome [82]. Nonetheless, recent studies on oxidative stress-induced diet reported weak or no apparent association in modifying the cardiovascular risk in an animal model (normotensive wild-type mice, C57BL/6 J), at least in its impact on systemic blood pressure [113].

The inconsistency in the reports of the potential neuroprotective effects of antioxidant (natural vitamin E) in cerebrovascular disease is partly due to the apparent lack of optimization in terms of concentrations/doses of the vitamin E used. This is despite the supportive data on supra(optimal)-physiological concentration of vitamin E (especially α-tocotrienol) that can interrupt the superoxide and NO reaction [108] to reduce the activation of ROS and endpoint BBB disintegration in CSVD. Hence, we are tempted to posit that appropriate nutritive consumptions of vitamin E could prove advantageous to attenuate BBB damages that underlie CSVD heterogenous manifestations, i.e., by halting the leukocyte-EC adhesion that can further degrade the BBB damages with WMHs. Biomarkers of oxidative stress can serve to monitor the redox imbalance in individuals with WMHs while exploring the putative therapeutic avenue with targeted dietary supplements as neuroprotective potentials against CSVD onset and/or disease manifestations. As such, the vitamin E neuroprotective merits could prevent a comprising reduction of cBF in cerebral ischemia in numerous CSVD manifestations, be it silent or symptomatic, from the ROS-centric targeting (**Figure 6**).

#### **5. Challenge and future direction**

Although data on therapeutic regimes had shown promising increased plasma levels of antioxidants, whether this translates to increased levels in the vasculature remains unknown. Even if sufficient levels of antioxidants were achieved in vascular cells, the antioxidants might in fact exert prooxidant effects as a result of their conversion to radical species following their reactions with superoxide [114, 115]. Either way, a single approach of conventional antioxidant supplementation would be suboptimal in combating oxidative stress in CSVD [108].

Corroboratively, with multiple studies having successfully linked the potential therapeutic and neuroprotective potentials of vitamin E in vascular health domains, a multicenter and adequately powered clinical trial is much needed for CSVD. Such data would further strengthen the nutritive value of vitamin E for CSVD neuroprotective supplements. In addition, opportunities exist to examine the connectivity of white matter tracts to exhibit vitamin E role in protection of small vessel collateral circulation as well as an increased expression of proarteriogenic (new blood vessel formation) genes in future research.

#### **6. Conclusion**

CSVD, as the commonest neurological condition as we age, could benefit from the potency of vitamin E antioxidant neuroprotective potentials through oxidative stress and BBB integrity modulation. This chapter converges contemporary

*Neuroprotection - New Approaches and Prospects*

whereby vitamin E supplementation had been shown to reduce the onset of WMHs in small clinical trials [109]. Moreover, natural vitamin E also had been shown favorable to lessen cognitive impairments in CSVD animal models

*Putative neuroprotective potentials of natural vitamin E in targeting ROS in CSVD manifestations. αTCT, α-tocotrienols; αTOC, α-tocopherols; ECs, endothelial cells; BBB, blood–brain barrier; ECM, extracellular matrix; cBF, cerebral blood flow; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; RNS, reactive nitrogen species; COX, cyclooxygenase; NADPH, nicotinamide adenine dinucleotide phosphate; MPs, microparticles; TNF-alpha, tumor necrosis factor-alpha; WMHs, white matter* 

*hyperintensities; CMBs, cerebral microbleeds; AD, Alzheimer's disease.*

**198**

**Figure 6.**

evidence to shed plausible insights on the neuroprotective potentials of natural vitamin E in addressing the heterogenous CSVD spectrum, in health and disease.
