|Year : 2020 | Volume
| Issue : 2 | Page : 35-42
Neuroprotective Effects of Co-administration of Coenzyme Q10 and Vitamin-E in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rats
Mahmoodullah Azimi1, Abdelkader E Ashour2, Azliana Abd Fuaat2, Wael M.Y Mohamed3
1 Department of Basic Medical Sciences, Kulliyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang; Clinical Pharmacology Department, Kabul University of Medical Sciences, Kabul, Afghanistan, Malaysia
2 Department of Basic Medical Sciences, Kulliyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang, Malaysia
3 Department of Basic Medical Sciences, Kulliyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang; Clinical Pharmacology Department, Menoufia Medical School, Menoufia University, Egypt, Malaysia
|Date of Submission||03-Dec-2019|
|Date of Decision||16-Dec-2019|
|Date of Acceptance||10-Feb-2020|
|Date of Web Publication||10-Apr-2020|
Wael M.Y Mohamed
Department of Basic Medical Sciences, Kulliyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan-25200, Pahang
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Alzheimer’s disease (AD) is the most common type of neurodegenerative diseases. Currently, there is no prevention or cure for AD. The potential use of natural antioxidants for prevention and treatment of AD has attracted considerable attention. Here, we used combination of the antioxidants coenzyme Q10 (CoQ10) and vitamin-E (Vit E) for the protection against AD. The current study assessed the neuroprotective effects of combination of CoQ10 with Vit E in Chronic Cerebral Hypoperfusion-induced neurodegeneration (CCH-ND) rat model. After acclimatization, 27 Sprague Dawley rats weighing 220–250 g were divided into six groups; sham control, 2-vessel occlusion (2VO), 2VO+E (treated daily with Vit E, 100 mg/kg, orally following 2VO), CoQ10 (treated daily with CoQ10, 200 mg/kg, orally following 2VO), CoQ10+E (treated with combination of CoQ10 and Vit E, orally following 2VO) and last group was treated with coconut-oil as a vehicle control. On the 8th week, all rats were tested by Morris water maze cognitive test and then euthanized and the hippocampi were isolated. Viable neuronal cell count in the hippocampal region was estimated. The Isoprostane F2 (F2-IsoPs) levels were assessed in the brain homogenates to quantify the oxidative stress status. There was significant difference in neuronal cell death, memory and learning, and F2-Iso level in untreated 2VO group compared to the treated and sham groups. However, there was no statistically significant difference in neuroprotective effects of combination of Vit E with CoQ10 and each one alone. To conclude, combination of the antioxidants (Vit E and CoQ10) improves memory, neuronal cell viability and decreases antioxidant level, same as each antioxidant alone.
Keywords: Alzheimer’s disease, cerebral hypoperfusion, coenzyme Q10, vitamin E, combination of antioxidants
|How to cite this article:|
Azimi M, Ashour AE, Fuaat AA, Mohamed WM. Neuroprotective Effects of Co-administration of Coenzyme Q10 and Vitamin-E in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rats. Int J Nutr Pharmacol Neurol Dis 2020;10:35-42
|How to cite this URL:|
Azimi M, Ashour AE, Fuaat AA, Mohamed WM. Neuroprotective Effects of Co-administration of Coenzyme Q10 and Vitamin-E in Chronic Cerebral Hypoperfusion-Induced Neurodegeneration in Rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2021 Jan 18];10:35-42. Available from: https://www.ijnpnd.com/text.asp?2020/10/2/35/282290
| Introduction|| |
Neurodegenerative disorders are characterized by chronic progressive loss of neurons and synapses in central nervous system. Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative diseases which is characterized by insidious and progressive loss of cognitive functions and neurons particularly in the hippocampus., In addition, AD is the most prevalent cause of dementia as there were 46.8 million people worldwide living with dementia in 2015 and 50 million in 2016. This number is anticipated to reach 131.5 million in 2050. The prevalence of dementia in Malaysia is expected to be 0.126% and 0.454% in 2020 and 2050 respectively The underlying pathophysiology of AD includes loss of neurons and synapses in the cerebral cortex, hippocampus and deposition of extracellular amyloid containing the β-amyloid protein (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein., Despite of different initiating events in pathogenesis of AD, the most common features are oxidative stress and inflammatory response which are directly damaging to the neurons., Another underlying pathophysiological abnormality is chronic reduction of blood supply to the cortical area of the brain due to different forms of vascular insufficiency that may trigger a chain of events that can cause neuronal dysfunction and cognitive impairment. A continuous decrease in regional cerebral blood flow (CBF) impairs memory process and augments dementia.
Permanent occlusion of both common carotid arteries of rats (2-Vessel Occlusion, 2VO) has been introduced as a model to mimic the cerebral hypoperfusion occurring in aging humans and AD. The relationship between altered CBF, mainly in the parietal and temporal cortices, and AD has been confidently established and certified. In 2VO model, chronic cerebral hypoperfusion occurs in the brain due to permanent ligation of bilateral common carotid arteries. This condition leads to neuronal cell death. The most injured neurons have been found in CA1 region of hippocampus as well as cerebral cortex that is principally accountable for cognitive function.
Vitamin E (Vit E) works as a biological scavenger of different free radicals. By functioning as anti-oxidant, eight different types of compounds closely related in chemical structure to Vit E have been found, namely (α, β, γ, δ) tocopherols and (α, β, γ, δ) tocotrienols. Vit E is effective in prevention of lipid peroxidation and other radical driven oxidative events. Laboratory and animal studies have showed a possible role for Vitamin E in the prevention and treatment of neurodegenerative disorders.,, Between the two isoforms of Vit E, tocotrienol demonstrates more antioxidant activity in both in vitro and in vivo models of several chronic diseases.,
Coenzyme Q10 (CoQ10) is an endogenously produced antioxidant and is a major component of electron transport chain (ETC) in the inner membrane of mitochondria. It is an important electron and proton carrier in the mitochondrial respiratory chain (MRC), taking electrons from complexes II and I, transferring them to complex III, and contributing to the ATP biosynthesis. Moreover, CoQ10 is needed for the stability of complex III in the MRC, works as an antioxidant in cell membranes, and is involved in many aspects of cellular metabolism. It is one of the promising agents for treatment of AD.,
F2-isoprostanes (F2-IsoPs) are formed in vivo by free radical-mediated attack on arachidonic acid followed by oxygen insertion. The 8-iso-prostaglandin F2α is a lipid peroxidation product of arachidonic acid and it is the most useful biomarker of oxidative damage. Brain F2- IsoPs are reproducibly elevated in AD patients at both dementia and prodromal stages of disease.
Currently available treatments for AD only improve the disease symptoms but do not treat the underlying pathophysiological processes., Numerous evidences have revealed the presence of oxidative stress in the beginning and progression of AD., Therefore, the potential of using natural antioxidants for prevention and treatment of AD has attracted considerable attention. Few studies have focused on antioxidant combination therapy of AD, including cell culture, animal models of neurodegeneration and even clinical trials, had promising and significant results compared to use of single antioxidant.,,,, However, whether the combination of CoQ10 with Vit E can protect against neurodegeneration has never been reported. The current study was designed to assess the neuroprortective effects of co-administration of CoQ10 and vitamin E in Chronic Cerebral Hypoperfusion-induced neurodegeneration (CCH-ND) rat model.
| Methodology|| |
All experimental procedures were approved by the ethical committee of International Islamic University Malaysia (IIUM). Forty two male, seven weeks old 230g to 280 g, Sprague Dawley (SD) rats were obtained from the faculty of Veterinary Medicine, University Putra Malaysia. All rats were housed in cages (two rats per cage) at 26±1°C and 12 hour light/dark cycle. All animals were fed with normal rat food pellets and tap water ad libitum. The animals were adapted for one week and then were randomly divided into 6-groups as follow:
Group A (n = 3): Rats with sham operation without permanent, bilateral common carotid arteries occlusion (2VO procedure). Group B (n = 3): Rats underwent 2VO procedure without treatment. Group C (n = 6): Rats with 2VO procedure and treated daily with Vit E (100 mg/kg, orally). Group D (n = 6): Rats with 2VO procedure and treated daily with Coenzyme Q10 (200 mg/kg, orally). Group E (n = 6): Rats with 2VO procedure and treated daily with combination of CoQ10 with Vit E (100 mg/kg Vit E + 200 mg/kg CoQ10). Group F (n = 3): Rats underwent 2VO procedure and treated with 1 ml coconut oil, daily. After eight consecutive weeks of treatment, rats were euthanized and brains were dissected and hippocampi were used for histopathological and immunological studies.
Coenzyme Q10 (Ubiquinone-10; CoQ10) in powder form was purchased from Xian Pincredit, China and stored at ≤4°C. CoQ10 solution was freshly prepared daily by adding 100 mg of Coenzyme Q10 powder in 1 ml of 50°C pre warmed coconut oil and then stirred for 15-30 minutes in order to dissolve completely. Vit E in the form of tocotrienol mixture was kindly supplied by Excelvite Sdn.Bhd. EvNo Supra Bio 25% is a natural full spectrum tocotrienol/tocopherol complex which was used in this study (100 mg/kg). It is constituted of naturally occurring mixture of tocotrienol and tocopherol extracted and was concentrated from red palm fruits (Elaeis guineensis). The tocotrienol/tocopherol mixture had the following composition: tocotrienol (78 %) and tocopherols (22%). All drugs were given orally via oral gavage in early morning daily for 8 consecutive weeks.
Cerebral hypoperfusion (2VO)
Surgery was done as described before. Briefly, under full aseptic conditions rats were anesthetized with intra-peritoneal injection of a mixture of ketamine (90 mg/kg) with xylazine (13 mg/kg). After checking the reflexes for surgery phase of anesthesia a 2–3 cm ventral midline skin incision was made in the neck area just above the sternal bone. After gentle tweezing of neck muscles, the carotid artery inside the carotid sheath located on both sides and the common carotid arteries were carefully separated from the vagus-nerve after cutting the carotid sheath. The common carotid arteries were double ligated by sterilized silk suture just below the bifurcation into internal and external carotid arteries and the arteries were cut between the two ligatures. The incision was stitched and the wound was treated with povidone iodine (‘Betadine’) solution. The body temperature was maintained throughout the surgical procedure and recovery period by heat lamp until the rats had full recovery from the general anesthesia. Cardiovascular and respiratory symptoms were monitored during and after the operation. Water and food were given when the rats became fully conscious. The treatment was started at the first postoperative day (day1).
Morris water maze (MWM) test
The Morris water maze (MWM) is a test of spatial learning for rodents that relies on distal cues to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. Spatial learning is assessed via repeated trials and reference memory is determined by preference for the platform area when the platform is absent. A modified model of MWM was employed in which a circular black fiberglass tank, 2 m in diameter, was used. The height of the tank was 60 cm and water was filled up to 30 cm. A black 10 cm in diameter cylindrical escape platform (EP) was used as target Rescue Island for the rats during the test. The water temperature was maintained at 26 ± 1°C throughout the training sessions and test trials, while changing the water periodically. We used floor up light and dim light. The illumination level of the study room was around 200 Lx. Colored posters were affixed to the walls surrounding the pool serving as extra-maze visual cues for the rats to orient themselves to the surrounding space and build up their spatial memory. Care was taken to avoid direct light, deposition of urine or fecal debris inside the pool to prevent development of olfactory cues. Rats swimming time, distance and speed were tracked, recorded and analyzed using Noldus EthoVision XT version 11.5 video tracking software (USA).
Spatial training phase
The animal was placed in the desired start up position in the maze, facing the tank wall. The animal was released into water at water-level. A timer and a computer-tracking program were started the moment the animal was released. The timer was stopped when the animal reached the platform within 2 minutes trial. When the animals did not find the platform within time limit they were either placed on the platform or guided to it. The animal was left on the platform during the inter-trial interval (ITI) for 15 second with the objective of allowing the rat to orient to its position in space and remember the position of the goal in relation to surrounding cues.
Then the animal was released again in the maze from a new start location. This was repeated until the animal had four trials per day for four subsequent days. [Table 1] shows the randomization of starting points.
Reference memory: probe trial
On day six, after 24 hours of the last acquisition trial, the platform was removed. Animals were placed in the east start position in the maze, facing the tank wall at the farthest point from the original platform position. A novel start position was used during the probe trial to ensure that its spatial preference is a reflection of the memory of the goal location rather than for a specific swimming path. The animal was removed after a fixed interval of 60 seconds. The object of the probe trial was to determine whether the animal remembers where the platform was located. Parameters of this test are number of platform-site crossovers, time and distance spent in the target quadrant compared with the other quadrants. Percent time or percent distance in the target quadrant was measured.
Euthanization of the rats was humanly done by overdose of diethyl ether inside a closed glass chamber until termination of respiration. Then rats were transferred to the theater room where brains were removed. The two brain hemispheres were divided through longitudinal cut between them. The left hemisphere was fixed in 10% formal saline for histopthological studies. The right hemisphere was further dissected to isolate the hippocampus with Dumont forceps. Hippocampi were then washed with ice cold water, dried and stored in Eppendorf tube at −80 °C till using them for immunological studies (ELISA) to quantify the level of F2-IsoPs in the hippocampus.
The data were analyzed by using Statistical Package for Social Sciences (SPSS) version 21 software and presented as mean± SEM values. P-value of less than 0.05 (P < 0.05) was considered statistically significant, mean value comparison was carried out using one-way Analysis of Variance (ANOVA).
| Results|| |
Morris water maze tests results
Latency time to find the hidden platform
As shown in [Figure 1], there was no statistically significant difference in latency time (in seconds “s”) to find the hidden platform between the CoQ10 and Vit E combination treated group (52± 4.8 s) as compared to Vit E group (65±4.5), CoQ10 treated group (55.3±2.3 s) and sham operated group (41.6±4.9 s). The CoQ10 and CoQ10 and Vit E combination treated groups had a significantly less time to find the hidden platform (p<0.05) as compared to the untreated 2VO group (92.6 ± 13.3 s). There was no statistically significant difference (p<0.05) between vitamin E treated group and coconut oil treated group (75.9±5.6 s) and untreated 2VO group.
|Figure 1 Bar chart illustrates latency times to find the hidden platform region for all study groups (€P<0.05, SHAM vs 2VO), (*P<0.05, 2VO vs 2VO+CoQ10), (*P< 0.05, 2VO vs 2VO+E+Q10). Results are expressed as mean ± SEM|
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Distance moved in trials
As shown in [Figure 2], there was no statistically significant difference in means of distance moved (in meters), between CoQ10 and Vit E combination treated group (1.144± 0.24 m) and Vit E treated group (1.43± 0.25 m), CoQ10 treated group (1.216± 0.16 m) or sham operated group (0.915±0.2 m). The CoQ10 and CoQ10 and Vit-E combination treated groups had moved a significantly less distance (P < 0.05) as compared to the untreated 2VO group (2.037 ± 0.2 m). There was no statistically significant difference (P < 0.05) between Vit E treated group and coconut oil treated group (1.66± 0.25m) and untreated 2VO group.
|Figure 2 Bar chart showing mean distance moved in meter for all study groups. (€P<0.05, sham vs 2VO), (*P<0.05, 2VO vs 2VO+Q10), (*P<0.05, 2VO vs 2VO+Vit E+CoQ10). Results are expressed as mean ± SEM|
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In the 6th day of test the platform was removed from the pool and the animals were released from the east side of the pool and allowed for one minute to swim. The amount of time, they spent at platform quadrant (south west) and crossing the platform zone was calculated and compared for all groups. There was no statistically significant difference in the time spent in platform quadrant between combination treated group (23.7± 3.5 s) and Vit E (21.9± 2.1 s), CoQ10 group (20.6 ±3.5 s), sham (22.3± 2.18 s), 2VO (19.5±2.5) or coconut oil group (19±1 s).
| Histopathology Results|| |
Neuronal cell count in the hippocampus
As shown in [Figure 3], upon histopathological examination of the hippocampi under light microscope at (40x) magnification power, there was discrimination between viable and non-viable pyramidal cell bodies within 1 mm horizontal distance of CA1 region. Viable pyramidal neurons typically are triangular in shape, which have well demarcated boundaries with a clear distinct nucleus and a relatively lightly stained cytoplasm. On the other hand, shrunken pyramidal cells, which showed poorly defined, irregular neuronal cell membrane with dark pyknotic cytoplasm and indistinguishable nucleus were considered non-viable neurons.
|Figure 3 Pyramidal cells within 1 mm of CA-1 region of hippocampus under high power magnification (40x) in different groups of study Sham (A), 2VO (B), Vit E(C), CoQ10 (D), Combination group (E)|
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There was no statistically significant difference (P < 0.05) in number of hippocampal viable pyramidal cells between the combination group (93.4± 6.5) and vit E group (97.6± 2.6), CoQ10 treated group (94.6± 4.8) or sham operated group (99.3± 6.5). These all treated groups (Vit E, CoQ10 and combination) had a significantly high number of viable pyramidal cell (P < 0.05) in comparison to the untreated 2VO group (41 ± 2). There was no statistical significant difference (P < 0.05) between coconut oil treated group (46.5 ± 1.5 pg/ml) and untreated 2VO group.
Immunological Assay ResultsIsoprostane F2 levels
As shown in [Figure 4], there was no statistically significant difference (P > 0.05) in hippocampal level of F2-Isorostane between the combination group (11± 1.2 pg/ml) as compared to Sham operated group (5± 2 pg/ml), Vit E group (10 ± 1.3 pg/ml) and CoQ10 treated group (11.2 ± 1.16 pg/ml). These treated groups have a significantly reduced F2-IsoPs levels (P < 0.05) compared to the untreated 2VO group (34 ±3 pg/ml) (Figure 8). There was no statistical significant difference (P > 0.05) between coconut oil treated group (26 ± 4.2 pg/ml) and untreated 2VO group.
|Figure 4 Bar chart depicting the hippocampal F2-IsoPs level in F2-IsoPs level in for all study groups. Data represents the (mean ± SEM) and (£P<0.05, SHAM vs 2VO), (#P<0.05, 2VO vs 2VO+E), (*P<0.05, 2VO vs 2VO+Q10), (€P<0.05, 2VO vs 2VO+E+Q10)|
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| Discussion|| |
The aim of study was to investigate the neuroprotective effects of combination of the antioxidant Vit E and CoQ10 in CCH induced ND model of rats. In this regard, we assessed and compared memory and learning by Morris water maze test, neuronal cell viability and level of oxidant (F2-isoprostane) in hippocampal area in all groups. The current study showed that Vit E improved memory and learning and cell viability and decreased oxidant level compared to untreated 2VO group. Our results are in agreement with those reported by Annaházi et al. and Mohamed et al., Furthermore, our results showed that CoQ10 improved memory and learning, cell viability and decreased oxidant level Compared to untreated 2VO group. Our findings are in accordance with those demonstrated by Kwong et al. and Hashemzadeh et al., Importantly, we showed for the first time that the combination of Vit E with CoQ10 improved memory and learning and cell viability and decreased oxidant level compared to untreated 2VO group. There was no statistically significant difference in memory and learning, number of hippocampal viable pyramidal cell and oxidant levels between CoQ10-Vit E treated group and Vit E treated group, CoQ10 treated group and Sham operated group. Also, there was no statistically significant difference in cognitive functions, number of hippocampal viable pyramidal cell and oxidant level between the coconut oil (vehicle) treated group and untreated 2VO group.
As several evidences have revealed oxidative stress in the beginning and progression of AD,, the potential of using natural antioxidants for prevention and treatment of AD has attracted considerable attention. Despite significant results in experimental studies, which used single antioxidants in AD models, clinical trials have failed to recapitulate the promising outcomes documented in animal studies., It is conceivable that the therapeutic regimen employing single antioxidants may not be sufficient to halt the neuropathologic process of AD. Therefore, an efficient strategy would be the use of combination of antioxidants in the treatment of AD to provide synergistic effects and enough antioxidant action without the need for using large and toxic doses of single antioxidant.,, A number of studies including cell culture, animal models of neurodegeneration and even clinical trials that used combined therapy of anti-oxidants had promising and significant results as compared to use of single antioxidants.,,,, However, these studies have used different models or different antioxidants. For instance, Shetty and his colleagues found in their study that both Vit E and CoQ10 improved the performance of aged mice in a learning task and Vit E + CoQ10 was more effective than either antioxidant alone at decreasing protein oxidation in peripheral tissues and certain brain regions. In another study of animal model of neurodegeneration, Yang et al. concluded that the combination of CoQ10 and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 Huntington’s disease mice. Moreover, the findings of McDonald and his colleagues suggest that concurrent supplementation of Vit E with CoQ10 is more likely to be effective as a potential treatment for age-related learning deficits than supplementation with CoQ10 or Vit E alone.Although we could not find a statistically significant difference between combination therapy of antioxidants and single antioxidant in CCH induced model of ND, we cannot say that combination of antioxidant has no additional neuroprotective effects than using single antioxidants alone. This is because there was no statistically significant difference between sham group (negative control) and all three groups treated with combination, Vit E or CoQ10 alone). This reveal that all treated groups, whether single anti-oxidants or combination group reached their maximum neuroprotective effects, same as shame group. In addition, in previous studies involving animal models of AD, Vit E and CoQ10 had significant neuroprotective effects, same as in sham operated group (which is similar to the present study results), but in clinical trials they had less effects. From current study at least we can conclude that this combination of antioxidants has no negative effects and in clinical trials it may have more neuroprotective effects than using single antioxidants. Furthermore, it is possible that our current sample size was small and this can be improved in future studies. Therefore, we suggest further work with a bigger sample size and clinical trials that use a combination of antioxidants especially the combination of Vit E and CoQ10, which potentially work synergistically and regenerate each other.
| Conclusion|| |
To conclude, there was no statistically significant difference in the neuroprotective effects of combination of Vit E with CoQ10 and each one alone in chronic cerebral hypoperfusion-induced neurodegeneration in rats. On the other hand, all these treated groups had maximum effects, same as those seen in the sham control group which is considered to be a significant improvement compared to 2VO untreated group. To the best of our knowledge, this is the first experimental study that examines the neuroprotective effects of combined administration of Vit E and CoQ10 in chronic cerebral hypoperfusion-induced neurodegeneration model in rats. However, we suggest further animal studies with larger sample size and clinical trials to study the effects of a combination of antioxidant especially combination of Vit E and CoQ10.
Financial support and sponsorship
Conflicts of interest
The authors declare that they do not have any conflict of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]