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Year : 2018  |  Volume : 8  |  Issue : 2  |  Page : 47-52

Oxidative Stress Status and Neuroprotection of Tocotrienols in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration Rat Animal Model

1 Department of Basic Medical Sciences, Faculty of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang, Malaysia; Department of Clinical Pharmacology, Menoufia Medical School, Menoufia University, Menoufia, Egypt
2 Department of Basic Medical Sciences, Faculty of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang, Malaysia

Date of Web Publication26-Apr-2018

Correspondence Address:
Wael M.Y Mohamed
Department of Basic Medical Sciences, Faculty of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang, Malaysia; Department of Clinical Pharmacology, Menoufia Medical School, Menoufia University, Menoufia, Egypt

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.ijnpnd_17_18

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Background: Reduced cerebral blood flow is associated with aging, neurodegenerative disorders, and an increased formation of reactive oxygen species. This study was designed to assess the potential use of vitamin E as an antioxidant and neuroprotective agent using 2-vessel occlusion (2VO) rat animal model. Materials and Methods: Twenty-four Sprague Dawley rats weighing 200–250 g were equally divided into the following three groups: SHAM control, 2VO, and 2VO+E (treated daily with vitamin E tocotrienol, 100 mg/kg, orally following 2VO). On the 8th week after 2VO surgery, rats were euthanized and the hippocampi were isolated with the estimation of viable neuronal cell count in the hippocampal CA-1 region. The isoprostane F2 (Iso-F2) levels were also measured in the brain homogenates to quantify the oxidative stress levels. Results: There was significantly higher neuronal cell death in the hippocampal CA-1 region and increased Iso-F2 levels in the 2VO group compared to the SHAM control group (P < 0.05). Conversely, no significant difference was observed with regard to the neuronal cell death and Iso-F2 levels in the 2VO+E group and the SHAM control group (P > 0.05). Conclusion: This study demonstrates the effectiveness of vitamin E tocotrienol as a neuroprotective and antioxidant agent in chronic cerebral hypoperfusion-induced neurodegeneration in rats.

Keywords: 2VO, brain dementia, cerebral hypoperfusion, tocotrienol

How to cite this article:
Mohamed WM, Sayeed S, Saxena AK, Oothuman P. Oxidative Stress Status and Neuroprotection of Tocotrienols in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration Rat Animal Model. Int J Nutr Pharmacol Neurol Dis 2018;8:47-52

How to cite this URL:
Mohamed WM, Sayeed S, Saxena AK, Oothuman P. Oxidative Stress Status and Neuroprotection of Tocotrienols in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration Rat Animal Model. Int J Nutr Pharmacol Neurol Dis [serial online] 2018 [cited 2022 Oct 4];8:47-52. Available from:

   Introduction Top

Neurodegenerative disorders (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease are characterized by a progressive and irreversible loss of neurons from specific regions of the brain.[1] AD, a leading cause of dementia, is a chronic progressive disorder, which affects millions of people worldwide causing loss of memory, reasoning, judgment, and even the ability to perform rudimentary daily tasks. Reduced cerebral blood flow (CBF), associated with aging and dementia,[2] leads to cerebral hypoperfusion with a compromised cognitive status. The prominent pathological hallmarks in neurodegeneration are the loss of neuronal cell bodies and synaptic contacts caused by altered blood supply to the brain. Chronic cerebral hypoperfusion (CCH) reduces energy supply to the brain and accelerates neuronal cell death and the loss of memory.[3] A model of CCH (as it occurs during aging and AD in humans) has been successfully introduced by permanent bilateral common carotid artery occlusion in rats [i.e., 2-vessel occlusion (2VO) rats].[4] 2VO rats have been used successfully as a model of vascular dementia with characteristic neuronal cell death in the hippocampus, cerebral cortex, white matter areas, and the visual system.[4],[5]

Neuronal cell death is aggravated due to the generation of highly reactive secondary aldehydes, namely the isoprostanes, by lipid peroxidation. These are prostaglandin-like compounds formed in vivo by the free radical-induced peroxidation of arachidonic acid. Among the various products of the isoprostanes are the F2-isoprostanes (F2-IsoPs), which are considered the most prominent biomarkers of oxidative stress (OS) status and lipid peroxidation in vivo. The quantification of these F2-IsoPs serves as a unique tool to assess the role of free radicals in human diseases and in the animal models of oxidative injury.[6] The best strategy to attenuate the effects of reactive oxygen species (ROS)-induced oxidative damage is through the use of antioxidant molecules.

A significant amount of research has been invested into the development of novel treatments capable of protecting the brain from damage prior to and following neurodegenerative diseases but with limited success. A wide range of neuroprotective agents have been ascertained that guarantee positive outcomes in the animal models of neurodegenerative diseases including, for example, vitamin C and vitamin E,[7] green tea polyphenols,[8] phytochemicals such as flavanoids,[9] alkaloids,[10] and coenzyme Q10.[11] However, we selected vitamin E for the current study for its unique promising biochemical and neuroprotective properties. Vitamin E is a broad term constituting a family of eight distinct compounds closely related in chemical structure, namely tocopherols and tocotrienols,[12],[13] which qualitatively exhibit the biological activity of alpha-tocopherol.[14] Tocotrienols have been poorly studied compared to tocopherols.[14],[15] The potential use of vitamin E tocotrienols as an antioxidant and neuroprotective agent in AD has been reported.[16],[17],[18],[19] The antioxidant ability of vitamin E arises from its lipophilic radical scavenging antioxidant activity in vivo.[20] Further, vitamin E acts as a signaling and gene regulation molecule[21] beside its ability to break the propagation of the free radical chain reaction in the lipid part of the biological membrane. It is noteworthy to mention that the half-life of vitamin E in the brain is long compared to other organs,[22] and its deficiency is associated not only with cell damage, but also is linked to ataxia, cognitive dysfunction, and impaired motor coordination.[23],[24],[25] Moreover, the anti-inflammatory activity of tocotrienols has been reviewed[26],[27] with the two isoforms of vitamin E, the tocopherols and tocotrienols. The latter has been reported to be more effective in scavenging free radicals in the neuroinflammation component of NDs. The present study was, therefore, designed to evaluate the neuroprotective and anti-inflammatory potential of vitamin E tocotrienol in the 2VO model of chronic cerebral hypoperfusion-induced neurodegeneration in rats.

   Materials and Methods Top


A total of 24 male white albino rats (Sprague Dawley-SD strain) weighing 200–250 g were obtained from Sapphire Enterprise, Selangor, Malaysia. During 1 week of acclimatization, rats were housed in pairs/cage in room with a 12 h/12 h dark/light cycle, and the temperature was maintained at 25 ± 2°C along with relative humidity (46–79%). Rats had free access to tap water and standard rat diet ad libitum. The institutional animal ethical committee approved this study; IACUC-IIUM and animals were treated in accordance with the Guidelines for the Care and Use of Laboratory Animals of the National Institute of Health.

After 1 week of acclimatization, rats were randomly divided into the following three groups: groups A, B, and C with 8 rats/group. Group A served as SHAM group or control group. The rats in-group B (2VO) had 2VO surgery without any treatment, and for group C (2VO+E), 2VO was performed with daily oral administration, via oral gavage tube, of vitamin E tocotrienol for 8 weeks (100 mg/kg body weight).

2VO procedure in rats

The 2VO surgery was performed as described before.[28],[29] Vitamin E in the form of tocotrienol mixture was supplied by Excelvite, (formerly known as Carotech Berhad), Chemor, Malaysia. Rats in group C (2VO+E) received oral vitamin E (100 mg/kg body weight) via oral gavage tube for 8 consecutive weeks in one single morning dose. At the end of the 8th postoperative week, all animals were sacrificed by euthanization with ether. The brains were isolated and dissected on ice-cold metal tray using cold instruments. The right hemisphere was dissected to isolate the hippocampus, washed with ice-cold water, and dried and stored in Eppendorf tube at −80°C for immunological studies. The left hemisphere was fixed in 10% formal saline at room temperature and processed in a tissue processor (Leica TP1020) before being prepared as wax paraffin blocks.

Preparation of the hippocampal brain sections and neuronal cell count

A wealth of studies discovered significantly higher neurodegenerative changes and a more distinct pyramidal cell loss in the CA-1 hippocampal area than the other brain areas of the 2VO rat model.[28],[30],[31] This is why we selected the CA-1 area, which has a selective vulnerability to neurodegenerative changes that were thought to be related to the relatively lower capillary vascularity and a more susceptible blood–brain barrier to leakage after significant reduction in CBF. Hence, the CA-1 region is more liable to excitotoxicity and later on neurodegeneration.[32] Briefly, on the paraffin-embedded blocks of the hippocampal brain, sections were cut at 5-μm thickness on a rotary microtome (Leica RM2235). The sections were stained with Cresyl violet.[18] Neuronal cell counting was performed on the sections stained with Cresyl violet using TEM (LIBRA 120-ZEISS Microscopy LLC, Thornwood, NY, USA). The number of viable neurons in the CA-1 region of the hippocampus (the cells of stratum pyramidale) was analyzed and counted within 1-mm horizontal distance of the CA-1 region of the hippocampus of all slides.[19] Viable pyramidal neurons in the CA-1 area are typically triangular in shape, with well-demarcated boundaries, a clear distinct nucleus, and a relatively lightly stained cytoplasm. Conversely, shrunken pyramidal cells, which showed a poorly defined, irregular neuronal cell membrane with a dark pyknotic cytoplasm and indistinguishable nucleus, were considered as nonviable neurons.

Estimation of lipid peroxidation

OS levels were measured by quantifying the F2-IsoPs levels in the hippocampus. The hippocampus after thawing was weighed and homogenized in phosphate buffer saline (PBS) with a glass homogenizer on ice. For every 1 g of tissue, 9 ml of PBS was added. The suspension was sonicated with an ultrasonic cell disrupter at high speed for 15 min to further break the cells. The homogenates were then centrifuged for 5 min at 5000×g to get the supernatant. Thereafter, the supernatant was collected and used to run enzyme linked immunosorbent assay to quantify the level of F2-IsoPs.

Statistical analysis

Data were expressed as mean ± standard error of mean (SEM). Results were analyzed using the Statistical Package for the Social Sciences version 20 software (SPSS Inc., Chicago, IL, United States). A P-value of <0.05 (P < 0.05) was considered significant. A mean value comparison of data for hippocampal neuronal cell count and hippocampal F2-IsoPs levels between SHAM, 2VO, and 2VO+E groups was performed via one-way analysis of variance followed by Dunnett’s test (Dunnett’s test was chosen to compare the mean of a control group with the mean of each group).

   Results Top

Histopathological results

Histopathological studies in the region of the hippocampus [Figure 1] showed obvious morphological differences among the various study groups. In the SHAM group, the viable neurons in the region revealed the compact cellular structure of stratum pyramidale with well-demarcated cellular membrane, clear cytoplasm, and distinct nucleus [[Figure 1]A]. In contrast, most of the stratum pyramidale in the untreated 2VO group displayed loose cellular arrangement with an irregular, dark, shrunken cytoplasm with pyknotic nucleus (nonviable neurons). Only a few cells had a viable nucleus. The cell density had drastically reduced with increased intercellular space, which indicates massive neuronal damage [[Figure 1]B]. The neuronal cells in the 2VO+E group showed almost similar characteristics as in the SHAM group. Vitamin E tocotrienol preserved the compact structure of stratum pyramidale and prevented loss of neuronal cells with less pyknotic nuclei, which showed less neuronal cell damage than the untreated 2VO group [[Figure 1]C].
Figure 1: Cresyl violet stained light photomicrograph depicting the dorsal hippocampal pyramidal cells of the CA-1 area. (A) SHAM, (B) 2VO group, and (C) 2VO+E group (400×)

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The viable pyramidal cell counts within 1-mm horizontal distance of the hippocampal CA-1 area for the SHAM group, 2VO group, and 2VO+E group were 265 ± 6.1, 121 ± 6.7, and 224 ± 5.3, respectively. There was a significant difference in the viable cell count between the 2VO group compared to the SHAM and 2VO+E groups (P < 0.05). However, the difference was insignificant between the numbers of viable cells of the 2VO+E group (vitamin E treated) compared to the SHAM group (P > 0.05).

Isoprostane F2 level measurement

As shown in [Table 1], the F2-IsoPs level in the hippocampus in the 2VO group (16.7 ± 0.5 pg/ml) was significantly higher (P < 0.05) compared to the SHAM group (4.4 ± 0.5 pg/ml). However, in the vitamin E tocotrienol-treated group (2VO+E), the F2-IsoPs levels (5.9 ± 0.3 pg/ml) had significantly reduced (P < 0.05) compared to the untreated 2VO group (16.7 ± 0.5 pg/ml).
Table 1: Hippocampal neuronal cell count and F2-IsoPs levels in the study groups (SHAM, 2VO and 2VO+E)

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   Discussion Top

With aging, in humans as well as animals, an impaired cerebrovascular system leads to a decrease in neuronal activity.[33],[34] Aging and AD including dementia are associated with reduced CBF,[2] which is believed to prompt the neurodegenerative processes. A significant amount of research on neuroprotection in AD was performed using animal models. Various methods for inducing AD in animals have been developed, and each is unique in its pathology and the effect of various neuroprotective agents. The 2VO model is highly suitable for the testing of potentially neuroprotective agents.[4] This is why we picked it as an animal model for the current study to produce brain injury via a variety of cellular and molecular mechanisms that mimic what happens during AD in humans.[34],[35]

OS is recognized to play a significant role in the advancement of many NDs because the brain is highly susceptible to lipid peroxidation due to its high oxygen utilization, low levels of antioxidants, and high levels of polyunsaturated fatty acids.[36],[37] An excessive release of free radicals leads to the development of OS, which is the root cause of various chronic and degenerative diseases.[38],[39] Antioxidants play an important role in diminishing the deleterious effects of ROS-induced oxidative damage. Vitamin E is a promising antioxidant, possessing many beneficial properties including neuroprotection and neuroinflammation.[9] Between the two isoforms of vitamin E, namely tocopherols and tocotrienols, the latter has been reported to exert superior antioxidant activity.[40] Palm oil-derived alpha-tocotrienol at nanomolar concentrations has been shown to attenuate both the enzymatic and nonenzymatic mediators of arachidonic acid metabolism and neurodegeneration.[41] Similarly, our results show that tocotrienol can significantly reduce the F2-IsoPs level in cerebral hypoperfusion-induced neurodegeneration. This clearly indicates that tocotrienols possess promising antioxidant activity in chronic cerebral hypoperfusion-induced neurodegeneration. This is in line with the study by Khanna et al.,[42] which reported the neuroprotective effect of natural vitamin E, alpha-tocotrienol, against glutamate- and stroke-induced neurodegeneration. However, they used mouse stroke model, which is totally different from our current 2VO model. With 2VO model, there is a sustained hemodynamic disturbance globally affecting the brain. The first (acute) phase of this disturbance is a short ischemic period. This is followed by a persistent, though less pronounced, reduction in CBF, which is referred to as the oligemic phase or the phase of chronic cerebral hypoperfusion. It is during the latter phase that the neurodegenerative process is thought to take place. The primary cerebral structures affected by 2VO-induced oligemia are the hippocampus followed by the cerebral cortex, which are the same two structures that were reported to suffer from progressive neurodegeneration in AD.[4] The major advantages of the 2VO model over the other models of cerebral hypoperfusion are that the 2VO model requires a more simple surgical preparation, that reperfusion can be readily accomplished, and that this model is easily suitable for chronic survival studies. This is why we selected 2VO model and targeted the hippocampus for the histopathological examination.[4]

Further, our results are in line with those of Khanna et al.,[43] who concluded that the oral supplementation of alpha-tocotrienol may protect neurons by an antioxidant-dependent mechanism. They used in-vitro cell culture, whereas the current study used in-vivo rat animal model, which is very close to what happens in a clinical setting. Additionally, the current results are in line with those of Frank et al.,[16] who reported that tocotrienols and tocotrienol-containing formulations at nontoxic levels had anti-inflammatory and neuroprotective effects in humans. However, our results are in contrast with clinical studies that failed to prove the neuroprotective effects of vitamin E.[44],[45] On the other hand, our findings concur with those of Osakada et al.,[46] who reported that alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons. Their findings further suggest that alpha-tocotrienol can exert antiapoptotic neuroprotective action independent of its antioxidant property.Our results showed a higher viable pyramidal cell count in rats treated with vitamin E compared to the untreated 2VO group. This implies a neuroprotective effect of vitamin E treatment opposing chronic cerebral hypoperfusion-induced neurodegeneration, considering the close similarity in the numbers of viable pyramidal neurons in the vitamin E treated group with that of the SHAM group [[Figure 1]B]. This comes in agreement with the study of Frank et al.,[16] who reported that tocotrienols, an isoform of vitamin E, significantly reduce the number of dead pyramidal cells after 3 weeks of transient global cerebral ischemia. The researchers of the aforementioned study have attributed such increase in viable hippocampal neurons to the antioxidant defensive property of vitamin E, which significantly lowered the OS parameters in the tocotrienol-treated group than that of the untreated group with transient cerebral ischemia. Further, the current results are consistent with those of Choi et al.,[47] who subjected rats to 2VO surgery. In this aforementioned study, significantly lower number of viable pyramidal cells were observed 8 weeks post 2VO in the untreated 2VO group compared to the SHAM group, which indicated significant neurodegeneration.

Although antioxidants act as nonspecific neuroprotectants and do not target specific pathological events, they are highly effective, and further investigations may lead to a more effective application of antioxidants. It will be of interest to know how antioxidants can interfere with signal transduction mechanisms. As long as specific interventions are not available, vitamin E tocotrienol could play an important role in the prevention and remedy of OS-induced conditions including AD. What is striking is that this neuroprotective effect was exhibited by a nutrient known to be safe for human consumption.

   Study Limitations and Future Work Top

Needless to say, our study has important methodological limitations resulting from the fact that it would be great to use an established antioxidant to compare with as a positive control. The current study is a small research report. The data provided in the study are preliminary in nature and need more exploration. For instance, it will be fruitful in future studies if we can measure gene expression and the protein expression of superoxide dismutase (SOD), LDH, as well as other stress markers in the different parts of the brain including the cortex, hippocampus, and amygdala. Additionally, there is an urgent need to design studies on the lesser-known forms of vitamin E with the emphasis on the mode of action of vitamin E molecule in vivo. The outcome of such studies would yield rewarding returns.

Financial support and sponsorship

Authors would like to thank IIUM Research Management Centre for sponsoring and supporting this research study (grant − EDW B 14-205-1090).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1]


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