{"id":54044,"date":"2023-12-31T11:38:08","date_gmt":"2023-12-31T11:38:08","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=54044"},"modified":"2024-01-05T06:10:51","modified_gmt":"2024-01-05T06:10:51","slug":"cognitive-enhancing-activities-of-coenzyme-q10-ramipril-and-vinpocetine-through-modulating-neuroinflammatory-response-and-oxidative-damage-inflicted-by-acute-rem-sleep-deprivation-in-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no4\/cognitive-enhancing-activities-of-coenzyme-q10-ramipril-and-vinpocetine-through-modulating-neuroinflammatory-response-and-oxidative-damage-inflicted-by-acute-rem-sleep-deprivation-in-rats\/","title":{"rendered":"Cognitive Enhancing Activities of Coenzyme Q10, Ramipril, and Vinpocetine Through Modulating Neuroinflammatory Response and Oxidative Damage Inflicted by Acute REM Sleep Deprivation in Rats"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Sleep\nis one of the fundamental conditions for quality of life\u00b9. Sleep is very\ncrucial in the formation and consolidation of memory.<\/p>\n\n\n\n

Many\nsleep disorders lead to memory problems. Impairment of cognition is seen even\nafter a single total night of sleep deprivation and can cause industrial, and transportation\naccidents and medical errors. REM and NREM sleep are the two phases of the sleep\ncycle. REM sleep has been reported mostly to be linked with memory and spatial\nlearning by enhancing hippocampal consolidation2,3 <\/sup>and can also\ncause  hyperphagia and weight loss4<\/sup><\/p>\n\n\n\n

Various\nneuropsychological studies and numerous behavioral studies on animals, such as the\nMorris water maze have been shown to cause cognition and memory deficits due to\nREM sleep deprivation2<\/sup>. With the increase in financial and social\nneeds of the \u2018modern global 24\/7 society, more people work outside their\nregular working time and ignore sleep. <\/p>\n\n\n\n

As per Reimund\u2019s free radical flux theory, sleep\npromotes endogenous anti-oxidant mechanisms activities and decreases the\nproduction of free radicals in the brain3<\/sup>. Thus, sleep essentially\nplays the role of a facilitator of antioxidants. Sleep deprivation has been\nproven to have a pro-inflammatory effect and its effects extend to the brain\nwhere cytokines like IL-1\u00df, IL-6, and TNF-\u00e0 are present5,6<\/sup>.<\/p>\n\n\n\n

Ramipril is a potent ACE (ACE \u2160). Angiotensin \u2161 is\nreduced by ACE \u2160 in the brain which inhibits the release of Acetylcholine and\nhas been proven to improve cognition7<\/sup>.<\/p>\n\n\n\n

Coenzyme Q10, a quinone compound is an electron\nacceptor in the ETC in the mitochondria membranes and has a central role in the\nchemi- osmotic synthesis. Coenzyme Q10 plays an important role\nin the process of cellular energy supply via oxidative phosphorylation within\nmitochondria. Treatment with\ncoenzyme Q10 has been proven to ameliorate cognitive deficits by modulating\nmitochondrial function 8<\/sup>. <\/p>\n\n\n\n

Vinpocetine, a nootropic alkaloid synthesized from\nperiwinkle acts as a neurotropic agent and reduces damage to the brain from\nischemia, stroke, and trauma. It improves memory and increases blood flow and\nmetabolism. <\/p>\n\n\n\n

This study has been conducted to study the effect of\nCoenzyme Q10, Ramipril and vinpocetine on cognition enhancement in REM sleep-deprived\ninsomniac rats.<\/p>\n\n\n\n

Materials and Method<\/strong><\/p>\n\n\n\n

Animals<\/strong><\/p>\n\n\n\n

Forty-eight\nmale Albino Wistar rats were selected for the study, which is locally bred in\nthe Central Animal House Research Facility <\/p>\n\n\n\n

To\navoid bias due to sex differences. In the Morris water maze, Male Wistar rats\nwere preferred. Three animals each were housed in a 41cm\u00d728cm\u00d714cm propylene\ncage. The animals are 8-10 weeks old and 200-250g weight, housed under\ncontrolled temperature conditions of 23\u00b12\u00baC, the humidity of 50\u00b15%, and light\nand dark cycle of 10-14 hours respectively. Each animal was housed separately in\npolypropylene cages containing sterile paddy husks (procured locally) as\nbedding throughout the study. Free access to sterile food (VRK nutritional\nsolutions, Pune, India) and water were given ad libitum. The study has been\ncarried out after it has been approved by Institutional Animal Ethics Committee\n(IAEC\/KMC\/40\/2021 dated 06.03.2021).<\/p>\n\n\n\n

The\nmarking of animals for identification was done using picric acid. The animals\nwere marked on the head, body, and tail using a cotton swab dipped in dilute\npicric acid. The markings were done accordingly as described in the experimental\nmanual.<\/p>\n\n\n\n

Drugs and Dosage<\/strong><\/p>\n\n\n\n

Ramipril (Lupin Ltd.), donepezil ( Intas Pharmaceuticals Ltd.), Coenzyme Q10 (Bulk Supplements), and Vinpocetine (Vivid Biotek Pvt Ltd.) were purchased from a local community pharmacy and were of analytical grade.<\/p>\n\n\n\n

Table 1: showing various groups, drugs dose, and routes used<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Group<\/strong><\/p>\n<\/td>\n

\n

Drugs, Dose And Route<\/strong><\/p>\n<\/td>\n

\n

Duration<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

REM sleep control animals<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

REM sleep deprived<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

REM sleep deprived + 2ml corn oil p.o<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

REM sleep deprived with donepezil 10mg\/kg\/day p.o<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

REM sleep deprived with vinpocetine 2mg\/kg\/day<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

REM sleep deprived with coenzymeQ10 10mg\/kg\/day dissolved in corn oil p.o<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

7<\/p>\n<\/td>\n

\n

REM sleep deprived with ramipril 10mg\/kg\/day p.o<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n

\n

8<\/p>\n<\/td>\n

\n

REM sleep deprived with coenzyme Q10 10mg\/kg\/day dissolved in corn oil + ramipril 10 mg\/kg \/day p.o<\/p>\n<\/td>\n

\n

1 week<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Coenzyme\nQ10, an electron acceptor in the ETC, and ramipril, an ACE inhibitor are used\nin this study. Doses of Coenzyme Q10(10mg\/kg), and ramipril (10 mg\/kg) were\ntaken from previous studies. Coenzyme Q10 50mg was dissolved in 30 ml corn oil\nand ramipril 50mg was dissolved in 30 ml distilled water.<\/p>\n\n\n\n

Experimental groups<\/strong><\/p>\n\n\n\n

Forty-eight\nanimals were divided into 8 groups equally<\/p>\n\n\n\n

Experimental design<\/strong><\/p>\n\n\n\n

Prior\nto experimentation, the animals were allowed to acclimatize to the laboratory\ncondition. Then, they were housed under a standard condition of 12h light\/dark\ncycle and were given standard rat feed and water ad libitum.<\/p>\n\n\n\n

REM sleep control<\/strong><\/p>\n\n\n\n

REM\nsleep control animals were evaluated using a modified multiple platform method.\nIn this method, the control animals(n=6) to be studied were placed on a\nplatform of diameter 6.5cm which is larger compared to the body size of the\nanimal. This allows the relaxed position for REM sleep. This is done to exclude\nstress due to isolation.<\/p>\n\n\n\n

REM sleep deprivation procedure<\/strong><\/p>\n\n\n\n

A\nmodified multiple platform is used for REM sleep deprivation which is a\nmodified version of the Inverted flower pot model. <\/em><\/strong>Here, the animals (REM\nsleep-deprived groups and treatment groups) are placed on a small platform of\ndiameter 5.5cm surrounded by water. This platform is small compared to the size\nof the body of the animal. REM sleep was disturbed for 24hrs every day for 1\nweek. The animals received the drugs in above table 1 for 1 week. This model is\nbased on the loss of muscle tone which accompanies REM sleep which is followed\nby the falling of the animals into the water. \nAfter sleep deprivation, the animal is subjected to learning and memory\nby the Morris water maze apparatus.<\/p>\n\n\n\n

Spatial learning and memory Assessment<\/strong><\/p>\n\n\n\n

Morris Water Maze<\/strong><\/p>\n\n\n\n

Morris water maze is used for the evaluation of learning and memory. The apparatus consists of a round tank (165cm \u00d7 135 cm). The tank is filled with water and maintained at 25\u00baC. Milk powder was added to make it non-transparent. The tank was divided into four equal zones (Z1, Z2, Z3, Z4) and the escape platform was placed in one of the zones submersed in water (water level 1cm below the platform). As a cue, Black and White boards were placed. Throughout the learning session, the extra maze cue and platform were placed at a fixed position 9<\/sup>.<\/p>\n\n\n\n

 It consists of 2 phases-          <\/p>\n\n\n\n

Spatial task acquisition phase<\/strong><\/p>\n\n\n\n

Each\nanimal was put through 4 consecutive trials with 2 min intervals, during which the\nstudy animal could leave from the platform and could remain there for 20secs\nfor 4 consecutive days. Animals will then undergo a series of trials using any\nof the start positions (Z1, Z2, Z3, Z4) randomly. If the animals are unable to\nlocate the platform even after 90secs then they are guided to the platform. The\ntime taken by each animal to reach the platform was counted.<\/p>\n\n\n\n

A\npreliminary test was conducted to familiarize the animals with the apparatus.<\/p>\n\n\n\n

b)Probe trial<\/strong><\/p>\n\n\n\n

On\nthe 5th<\/sup> day, the platform\/island is removed and the animal is\nallowed to traverse the pool for 90 sec to assess reference memory. Time spent in\nthe target zone was measured.<\/p>\n\n\n\n

Biochemical Analysis- for GSH,MDA and acetylcholinesterase activity was done<\/p>\n\n\n\n

 Statistical Analysis<\/strong><\/p>\n\n\n\n

One-way\nANOVA (Analysis of variance) followed by post hoc analysis using Tukey\u2019s test\nwas used for data analysis. Student\u2019s paired t-test is used to compare the\nresult before and after. The level of significance for any measure was set at\np<0.05 at a confidence level of 95%. Mean \u00b1 standard error of mean was used\nfor data expression.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Morris water maze results<\/strong><\/p>\n\n\n\n

Acquisition trials<\/strong><\/p>\n\n\n\n

In day 1 and day 2 acquisition trials, all groups were comparable to the time required to reach the hidden platform. On day 3 and Day 4, there was a significant decrease (p<0.001) in latency in coenzyme Q10 and ramipril-treated rats. There was also a significant decrease in latency (p<0.001) in the combination group SD +CoQ10+ Ramipril. [Table 2]\n\n\n\n

Probe trial<\/strong><\/p>\n\n\n\n

The percentage of time spent in the target zone was calculated:<\/p>\n\n\n\n

In the probe trial, as compared to the control, sleep-deprived rats showed a significant decrease (p<0.001) in the percentage spent in the target quadrant. Whereas there was a significant increase in percentage time spent in CoQ10, ramipril, and the combination of these two, donepezil and Vinpocetine as compared to sleep-deprived rats. (p<0.01).Combination of CoQ10 and Ramipril showed significant increase in percentage time spent. [Table 3]\n\n\n\n

Weight of animal<\/strong><\/p>\n\n\n\n

As compared to day 1, a significant decrease (p<0.05) in weight was seen in the sleep-deprived group, sleep-deprived (SD) with Corn oil compared to control. SD with CoQ10  and its combination with ramipril showed a significant increase in weight.[Table 4]\n\n\n\n

Table 2: Effect of CoQ10 and Ramipril on  REM sleep deprivation induced alteration in latency in MWM.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Groups<\/strong><\/p>\n<\/td>\n

\n

Acquisition trials-Latency in secs Mean\u00b1SEM<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Day1<\/strong><\/p>\n<\/td>\n

\n

Day2<\/strong><\/p>\n<\/td>\n

\n

Day3<\/strong><\/p>\n<\/td>\n

\n

Day4<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Control<\/p>\n<\/td>\n

\n

11.45\u00b10.47<\/p>\n<\/td>\n

\n

11.95\u00b10.44<\/p>\n<\/td>\n

\n

8.52\u00b10.42<\/p>\n<\/td>\n

\n

6.61\u00b10.25<\/p>\n<\/td>\n<\/tr>\n

\n

Sleep deprived (SD)<\/p>\n<\/td>\n

\n

23.97\u00b13.16<\/p>\n<\/td>\n

\n

12.33\u00b10.39<\/p>\n<\/td>\n

\n

11.44\u00b10.49<\/p>\n<\/td>\n

\n

12.49\u00b10.28\u204e<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD + Corn oil(CO)<\/p>\n<\/td>\n

\n

12.72\u00b10.70<\/p>\n<\/td>\n

\n

11.70\u00b10.43<\/p>\n<\/td>\n

\n

5.40\u00b10.40<\/p>\n<\/td>\n

\n

3.23\u00b10.34a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Donepezil<\/p>\n<\/td>\n

\n

16.90\u00b10.69<\/p>\n<\/td>\n

\n

12.41\u00b10.52<\/p>\n<\/td>\n

\n

6.76\u00b10.24<\/p>\n<\/td>\n

\n

3.17\u00b10.17a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Vinpocetine<\/p>\n<\/td>\n

\n

15.69\u00b10.51<\/p>\n<\/td>\n

\n

11.82\u00b10.38<\/p>\n<\/td>\n

\n

5.42\u00b10.40<\/p>\n<\/td>\n

\n

2.22\u00b10.13a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10<\/p>\n<\/td>\n

\n

17.64\u00b10.69<\/p>\n<\/td>\n

\n

12.21\u00b10.44<\/p>\n<\/td>\n

\n

6.31\u00b10.30<\/p>\n<\/td>\n

\n

2.54\u00b10.18a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Ramipril<\/p>\n<\/td>\n

\n

20.93\u00b10.42<\/p>\n<\/td>\n

\n

12.96\u00b10.55<\/p>\n<\/td>\n

\n

7.88\u00b10.22<\/p>\n<\/td>\n

\n

2.69\u00b10.17<\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10+R<\/p>\n<\/td>\n

\n

16.93\u00b10.42<\/p>\n<\/td>\n

\n

12.10\u00b10.53<\/p>\n<\/td>\n

\n

5.75\u00b10.95<\/p>\n<\/td>\n

\n

2.25\u00b10.12a<\/sup><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

One way ANOVA followed by Tukey\u2019s test \u204e<\/sup>p<0.001 vs control, a<\/sup>p<0.001 vs SD<\/p>\n\n\n

Table 3: Effect of CoQ10, Ramipril, and Vinpocetine on time spent in target zone in MWM.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Groups<\/strong><\/p>\n<\/td>\n

\n

Percentage time spent  in Target zone<\/strong><\/p>\n

 Mean \u00b1 SEM (%)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Control<\/p>\n<\/td>\n

\n

17.03 \u00b1 1.23<\/p>\n<\/td>\n<\/tr>\n

\n

Sleep deprived(SD)<\/p>\n<\/td>\n

\n

14.4 \u00b1 2.41\u204eb<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Cornoil<\/p>\n<\/td>\n

\n

10.50 \u00b1 1.14*b<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Donezepil<\/p>\n<\/td>\n

\n

15.46\u00b11.25<\/p>\n<\/td>\n<\/tr>\n

\n

SD+Vinpocetine<\/p>\n<\/td>\n

\n

17.14 \u00b1 0.43a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10<\/p>\n<\/td>\n

\n

26.64 \u00b1 3.25a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Ramipril<\/p>\n<\/td>\n

\n

24.93\u00b11.34a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10+ Ramipril<\/p>\n<\/td>\n

\n

18.96\u00b11.47*b<\/sup><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

One-way ANOVA followed by Tukey,s test<\/p>\n

*<\/sup>p<0.01 vs Control, a<\/sup>p<0.01 vs SD, b<\/sup>p<0.01 vs Donepezil.<\/p>\n\n\n

Table 4: Effect of CoQ10, Ramipril, and combination on body weight.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Groups<\/strong><\/p>\n<\/td>\n

\n

Body weight at Day1  (Mean\u00b1SEM)<\/strong><\/p>\n<\/td>\n

\n

Body weight at Day7 (Mean\u00b1SEM)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Control<\/p>\n<\/td>\n

\n

239.16 \u00b1 8.55<\/p>\n<\/td>\n

\n

257.83 \u00b1 5.03<\/p>\n<\/td>\n<\/tr>\n

\n

SD<\/p>\n<\/td>\n

\n

245.50 \u00b1 5.25<\/p>\n<\/td>\n

\n

205.00 \u00b1 5.89b<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD + Corn oil<\/p>\n<\/td>\n

\n

230.00 \u00b1 6.75<\/p>\n<\/td>\n

\n

253.12 \u00b1 7.59b<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+ Donepezil<\/p>\n<\/td>\n

\n

208.33 \u00b1 11.25<\/p>\n<\/td>\n

\n

205.66 \u00b1 5.89*<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Vinpocetine<\/p>\n<\/td>\n

\n

245.33 \u00b1 8.11<\/p>\n<\/td>\n

\n

236.33 \u00b1 9.03<\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10<\/p>\n<\/td>\n

\n

239.00 \u00b1 2.92<\/p>\n<\/td>\n

\n

232.66 \u00b1 3.29*a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+Ramipril<\/p>\n<\/td>\n

\n

194.00 \u00b1 10.74<\/p>\n<\/td>\n

\n

186.50 \u00b19.27*a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10+Ramipril<\/p>\n<\/td>\n

\n

216.16 \u00b1 5.78<\/p>\n<\/td>\n

\n

210.83 \u00b1 6.13*<\/sup><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 paired t- test *<\/sup>p<0.001 vs SD,a <\/sup>p<0.05 vs Control , b<\/sup>p<0.05 vs donepezil.<\/p>\n\n\n

Histopathology<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Legend: <\/strong>Representative photomicrographs of Cresyl violet stained hippocampal CA3 region of group 1 (control), group 2 (acute sleep deprivation), group 3 (Donepezil treated).<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Representative\nphotomicrographs of Cresyl violet stained hippocampal CA3 region of group 1\n(control), group 2 (acute sleep deprivation), group 3 (Donepezil treated) group\n4 (Vinpocetine treated), group 5 (Coenzyme Q10 treated), group 6 (Ramipril\ntreated) and group 7 (Ramipril + Coenzyme Q10 treated) [Magnification: 40×10 X]\n\n\n\n

It can be\nnoted that the number of degenerating pyknotic neurons (indicated by red arrow)\nwhich look characteristically flame-shaped (shown in red circle) are relatively\nmore in Group 2 when compared to those of other groups. A slight increase in\nthe healthy neurons (indicated by the yellow arrow) can be seen in groups 4, 6,\nand 7 when compared to group 2. However, group 5 showed a marked reduction in the\nnumber of flame-shaped pyknotic cells and a greater number of normal healthy\nneurons when compared to those of group 2.<\/p>\n\n\n\n

Qualitative analysis of Cresyl violet stained pyramidal neurons of hippocampal CA3 region<\/strong><\/p>\n\n\n\n

Cresyl violet\nstained pyramidal neuronal cell bodies of the hippocampal CA3 region of rats of\nthe control group (group 1) showed normal healthy neurons (indicated by yellow\narrow ) with a healthy-looking cell membrane, clear cytoplasm, and prominent\nnucleus. However, the Cresyl violet stained hippocampal CA3 region of the acute\nsleep-deprived group (Group 2) showed many degenerating, flame-shaped, pyknotic\ncell bodies of pyramidal neurons (indicated by red arrow). The flame-shaped\ncells which look deeply basophilic are indicative of karyopyknosis of the\nneurons of the hippocampus. It is noted that there is a marked increase in the\nhealthy neurons and a decrease in the flame-shaped, degenerating pyramidal\nneuronal cell bodies in the hippocampal CA3 region of rats belonging to groups\n4, 6, and 7 when compared to those of groups 2. However, group 5 showed a\nsubstantial increase in the number of healthy neurons and very few or\nnegligible numbers of flame-shaped, degenerating pyramidal neuronal cell bodies\nin the hippocampal CA3 region when compared to those of group 2.<\/p>\n\n\n\n

Dentate gyrus<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 2 Legend: <\/strong>Representative photomicrographs of Cresyl violet stained dentate gyrus of group 1 (control), group 2 (acute sleep deprivation), group 3 (Donepezil treated)<\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Representative\nphotomicrographs of Cresyl violet stained dentate gyrus of group 1 (control),\ngroup 2 (acute sleep deprivation), group 3 (Donepezil treated) group 4\n(Vinpocetine treated), group 5 (Coenzyme Q10 treated), group 6 (Ramipril\ntreated) and group 7 (Ramipril + Coenzyme Q10 treated) rats showing the cell\nbodies of the neurons. [Magnification: 40×10 X]\n\n\n\n

It can be\nnoted that the number of degenerating pyknotic neurons (indicated by red arrow)\nwith characteristic flame-shape (shown in red circle) are relatively more in\nGroup 2 when compared to those of other groups. A slight increase in the\nhealthy neurons (indicated by the yellow arrow) can be seen in Groups 4, 6, and\n7 when compared to Group 2. The number of flame-shaped pyknotic cells is\nmarkedly reduced in group 5 when compared to those of group 2.<\/p>\n\n\n\n

Qualitative\nhistopathological evaluation of Cresyl violet stained neurons of the dentate\ngyrus<\/strong>:<\/strong><\/p>\n\n\n\n

Cresyl violet\nstained dentate gyrus neurons of rats belonging to the control group (group 1)\nshowed normal healthy cell bodies (indicated by yellow arrow ).  Their plasma membrane looked healthy with\ndistinct edges. Cytoplasm was clear and the nucleus was easily recognizable. The\ngeneral arrangement of neurons also appeared normal. However, Cresyl violet\nstained dentate gyrus neurons of the acute sleep-deprived group (Group 2)\nshowed many pyknotic cell bodies of neurons with characteristic flame\u2011shapes.\n(encircled and indicated by the red arrow in the figure 2). Deeply basophilic\nflame-shaped cells indicate the degenerating nature of these neurons which\ncould be due to karyopyknosis. It is noted that there is a marked increase in\nthe healthy neurons and a decrease in the flame-shaped, degenerating neuronal\ncells of the dentate gyrus of rats belonging to groups 4, 6, and 7 when\ncompared to that of group 2. But, group 5 showed a substantial increase in the number\nof healthy neurons and very few or negligible numbers of flame-shaped,\ndegenerating neurons of dentate gyrus when compared to those of group 2.<\/p>\n\n\n\n

Table 5:<\/strong> Biochemical Analysis<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Groups<\/strong><\/p>\n<\/td>\n

\n

GSH (\u00b5M\/mg\/tissue)<\/strong><\/p>\n<\/td>\n

\n

MDA (nM\/g\/tissue)<\/strong><\/p>\n<\/td>\n

\n

AChE (\u00b5M\/min\/g tissue)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Control<\/p>\n<\/td>\n

\n

0.027\u00b10.01<\/p>\n<\/td>\n

\n

0.01367\u00b10.01<\/p>\n<\/td>\n

\n

2.346\u00b10.01<\/p>\n<\/td>\n<\/tr>\n

\n

SD<\/p>\n<\/td>\n

\n

0.01333\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

0.02817\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

3.848\u00b10.02*a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD + Corn oil<\/p>\n<\/td>\n

\n

0.01416\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

0.02513\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

3.446\u00b10.01*a<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

SD+ Donepezil<\/p>\n<\/td>\n

\n

0.01567\u00b10.02*,<\/sup>**<\/p>\n<\/td>\n

\n

0.01283\u00b10.01**<\/p>\n<\/td>\n

\n

2.351\u00b10.02**<\/p>\n<\/td>\n<\/tr>\n

\n

SD+Vinpocetine<\/p>\n<\/td>\n

\n

0.01817\u00b10.01a<\/p>\n<\/td>\n

\n

0.01533\u00b10.04*,<\/sup>**<\/p>\n<\/td>\n

\n

3.861\u00b10.03**<\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10<\/p>\n<\/td>\n

\n

0.02517\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

0.01285\u00b10.01<\/p>\n<\/td>\n

\n

2.835\u00b10.02**<\/p>\n<\/td>\n<\/tr>\n

\n

SD+Ramipril<\/p>\n<\/td>\n

\n

0.01417\u00b10.01a<\/sup><\/p>\n<\/td>\n

\n

0.01156\u00b10.01**<\/p>\n<\/td>\n

\n

2.836\u00b10.01**<\/p>\n<\/td>\n<\/tr>\n

\n

SD+CoQ10+Ramipril<\/p>\n<\/td>\n

\n

0.025\u00b10.03a<\/sup><\/p>\n<\/td>\n

\n

0.01455\u00b10.01<\/p>\n<\/td>\n

\n

2.834\u00b10.03**<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

One-way ANOVA followed by Tukey,s test<\/p>\n

*vs control,**vs SD, a <\/sup>vs Donepezil<\/p>\n\n\n

There was a significant decrease in GSH levels in the REM sleep-deprived donepezil group in comparison to the control (p\u02c20.05) and a significant increase (p\u02c20.05) in levels was seen in the REM sleep-deprived group alone. (Table 5)<\/p>\n\n\n\n

There was a significant decrease in MDA levels\nin the REM sleep deprived -donepezil group, vinpocetine group, and ramipril\ngroup in comparison to the REM sleep-deprived group alone (p\u02c20.05). (Table 5)<\/p>\n\n\n\n

The brain acetylcholinesterase level is\nsignificantly increased (p\u02c20.05) in REM sleep deprived alone and along with the\ncorn oil group in comparison to the control. Rats REM sleep deprived treated\nwith donepezil, vinpocetine, coenzyme Q10, ramipril, and coenzyme Q10 +\nramipril groups showed a significant decrease in acetylcholinesterase level in\ncomparison to  REM sleep deprived alone. (Table\n5)<\/p>\n\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

In this study, coenzyme Q10, ramipril, and\nits combination improve the memory impairment caused by acute sleep deprivation\n(total sleep deprivation -7 days) with everyday dosing. Spatial learning and\nmemory were assessed using the Morris water maze test. The data showed that\nacute REM sleep deprivation for 7 days impairs learning and memory.<\/p>\n\n\n\n

In the current study, sleep deprivation\nwas induced using a modified multiple platform model 10<\/sup>. It has the\nsame principle as the flower pot model i.e. loss of muscle tone during REM\nsleep. The data from the current study shows that REM sleep deprivation for 7\ndays impairs learning and memory. From various experiments performed by\ndifferent researchers earlier, we can conclude that REM sleep deprivation is\nassociated with cognition and that it causes cognitive impairment. From\nprevious studies, it has been seen that sleep deprivation using multiple\nplatform models impairs the acquisition rate as well as the ability to remember\nthe position in the probe trial 11<\/sup>.<\/p>\n\n\n\n

The multiple platform model still has some\ndrawbacks like it can be affected by stress and anxiety12<\/sup>. <\/p>\n\n\n\n

Studies have shown that RAS is involved in\nmemory and cognition 13<\/sup>. All mammalian brains, there is a role of\nRAAS with Angiotensin II plays an important neuromodulator role. Studies have\nshown ACEI enhancing retention performance in both short-term and long-term\nmemory behavioral tasks 14<\/sup>. Treatment with ACEI prevented impairment\nof memory, oxidative stress, and cholinergic dysfunction in rats.<\/p>\n\n\n\n

ACEI\nhas been proven to improve memory and cognition in previous studies15,16<\/sup>.\nThe role of Ramipril on learning and memory is evaluated in this study.\nRamipril 10mg\/kg significantly ameliorates cognition impairment caused by sleep\ndeprivation. The antioxidant activity with ramipril, an ACE inhibitor can be\nexplained by the blockade of reactive oxygen species by a RAS blocker involving\nthe angiotensin II signaling pathways, which results in the inhibition of\nreactive oxygen species 17<\/sup>.<\/p>\n\n\n\n

Due to oxidative stress in the brain,\nsuperoxide anion, hydroxyl radical and hydrogen peroxide are generated which\nact on PUFA & cause lipid peroxidation. Oxidative free radical scavenging\nenzymes like GSH, SOD, and catalase reduce oxidative stress in the brain. The\ncurrent study displays an increase in MDA and a decrease in total GSH following\nREM sleep deprivation suggesting free radical generation<\/p>\n\n\n\n

Alzheimer\u2019s disease patients there is an increase\nin cerebral ACE and angiotensin II and they promote neuroinflammatory cytokines,\nreduce acetylcholine release and decrease cerebral blood flow 18<\/sup>.<\/p>\n\n\n\n

Coenzyme Q10  is a powerful antioxidant, protecting cell\nmembranes from free radical induced oxidative damage. It also affects the\nexpression of genes involved in the inflammatory process. Since Coenzyme Q10 is\nan electron acceptor in ETC, produces ATP and hence is related to cognition and\ncognition decline. In this study, Coenzyme Q10 10mg \/kg significantly repairs\ncognition impairment. In Alzheimer\u2019s disease, one of the important factors in\npathogenesis is oxidative stress. So, Coenzyme Q10 offers some protection due\nto its antioxidant effect 19<\/sup> and increasing Coenzyme Q10\nconcentrations in the mitochondria of brain cells and facilitating the memory\nand learning processes in rats. In aging mitochondrial impairment and oxidative\nstress are important, they are also involved in the pathogenesis of Alzheimer\u2019s\ndisease-inflammation is caused by excessive production of ROS and contributes\nto the pathogenesis of Alzheimer\u2019s disease. Mitochondrial dysfunction has been\nassociated with the onset and development of neurodegenerative disease 20<\/sup>.\nBeneficial therapeutic effects of coenzyme Q10 have been seen in oxidative\nstress-mediated neurodegenerative disorders 21<\/sup>.<\/p>\n\n\n\n

A previous study by Sandhir et al\npresented that rats treated with Coenzyme 10 were able to locate the hidden\nplatform in the Morris water maze test, hence an improvement in cognitive\nfunction 22<\/sup>.<\/p>\n\n\n\n

Vinpocetine can cross the blood-brain\nbarrier and enter the brain after oral or intravenous administration. It improves\nblood flow by cerebral vasodilator action and also increases cerebral\nmetabolism by increasing oxygen and glucose uptake and stimulating neuronal ATP\nproduction. Also acts as an antioxidant and prevents the neurotoxic increase in\nsodium and calcium levels 23<\/sup>. Vinpocetine enhances spatial memory by\nmodulating the cholinergic system 24<\/sup>. Gupta et al.<\/em> found that treatment of vinpocetine reduced\nchronic cerebral hypoperfusion (CCH).ROS have been known to play the role in\nischemic injury and neurodegenerative disorders and their findings indicate\nthat vinpocetine enhances spatial memory through an antioxidant mechanism, the\nmodulation of cholinergic functions, and the prevention of neuronal cell damage\n25<\/sup>.<\/p>\n\n\n\n

The cognitive enhancement is due to PDE\ntype 1 inhibition, which increases CAMP and CGMP levels. These cyclic\nnucleotides in turn activate a series of kinases that phosphorylate the transcription\nfactors (CREB) and SRF, leading to the expression of plasticity-related genes.<\/p>\n\n\n\n

Accumulation of the amyloid-\u03b2 protein leads\nto an up-regulation of interleukins and TNF \u03b1. Vinpocetine\u2019s anti-inflammatory\nproperties may have a protective role in Alzheimer\u2019s disease.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

In this study, Coenzyme Q10, ramipril, and its combination are seen to improve learning and memory in acute sleep deprivation induced cognition impairment by behavioral, histopathological, and biochemical tests performed.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

I am thankful to the faculty of Central Animal Research Facility for helping in the conduct of the project ,Department of Biochemistry for chemicals for analysis and Ms. Shravya C for helping in the statistical analysis.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest.<\/p>\n\n\n\n

Funding Source<\/strong><\/p>\n\n\n\n

Received Postgraduate thesis grant from our Institute bearing number PGR557.<\/p>\n\n\n\n

References<\/strong><\/strong><\/p>\n\n\n\n

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    Abbreviations<\/strong><\/p>\n\n\n\n

    Gr.-group<\/p>\n\n\n\n

    REM-Rapid\neye movement <\/p>\n\n\n\n

    NREM-Non-rapid\neye movement<\/p>\n\n\n\n

    ACE\nI-Angiotensin converting enzyme inhibitor<\/p>\n\n\n\n

    ETC-Electron\ntransport chain<\/p>\n\n\n\n

    RAS-Renin\nangiotensin system<\/p>\n\n\n\n

    RAAS-Renin\nangiotensin aldosterone system<\/p>\n\n\n\n

    PUFA-Polyunsaturated\nfatty acid<\/p>\n\n\n\n

    GSH-Glutathione<\/p>\n\n\n\n

    SOD-Superoxide\ndismutase<\/p>\n\n\n\n

    MDA-Malondialdehyde<\/p>\n\n\n\n

    ATP-Adenosine\ntriphosphate<\/p>\n","protected":false},"excerpt":{"rendered":"

    Introduction Sleep is one of the fundamental conditions for quality […]<\/p>\n","protected":false},"author":15,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[111],"tags":[],"class_list":["post-54044","post","type-post","status-publish","format-standard","hentry","category-vol16no4"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/54044","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=54044"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/54044\/revisions"}],"predecessor-version":[{"id":55055,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/54044\/revisions\/55055"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=54044"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=54044"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=54044"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}