{"id":40872,"date":"2021-09-30T11:48:10","date_gmt":"2021-09-30T11:48:10","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=40872"},"modified":"2021-10-11T07:29:39","modified_gmt":"2021-10-11T07:29:39","slug":"cognitive-disorders-and-oxidative-stress-status-attenuated-by-chrysophyllum-perpulchrum-extract-in-alzheimer-like-rat-model-of-intracerebroventricular-a%ce%b21-40-injection","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol14no3\/cognitive-disorders-and-oxidative-stress-status-attenuated-by-chrysophyllum-perpulchrum-extract-in-alzheimer-like-rat-model-of-intracerebroventricular-a%ce%b21-40-injection\/","title":{"rendered":"Cognitive Disorders and Oxidative Stress Status Attenuated by Chrysophyllum Perpulchrum Extract in Alzheimer- like Rat Model of Intracerebroventricular A\u03b21-40 injection"},"content":{"rendered":"

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

Alzheimer Disease (AD) is the common form of dementia disorders which is mostly prevalent among ageing population through world. AD is a complex multi factorial neurodegenerative disease characterized by extracellular \u03b2-amyloid (A\u03b2) senile plaques deposition and\u00a0 intracellular neurofibrillary tangles of hyperphosphorylated Tau protein in selective brain areas as hippocampus and cerebral cortex,1<\/sup> causingmemory loss, progressive cognitive and mood disorders. According to one review of worldwide data, AD represents more than 60%\u00a0of all dementia in developing countries including those of Sub-Saharan Africa (SSA),2<\/sup> and the global dementia in people over 60 years is approximately 1.6% in Africa compared to 5.9% and 6.4% in western Europe and north America respectively.3\u00a0<\/sup>However, SSA countries\u00a0show some rapid demographic and economic transitions, and that is accompanied by an improvement of lifestyle quality. It could project to an increase of the life expectancy and the incidence of age-related neurodegenerative diseases as AD during upcoming years. Although entire mechanisms of the A\u03b2 neurotoxicity are still unclear, it has been considerably\u00a0demonstrated that the oxidative stress status plays a critical role in the physiopathogenesis of AD leading to neuronal death.4\u00a0<\/sup>Thus, a big challenge is to find out drugs with free radicals scavenging activity for helping to prevent cognitive and behavioral deficits related to oxidative\u00a0stress.Today, the most drugs classes approved for transiently slow down AD progression are from synthetic chemicals,5\u00a0<\/sup>with possibleexisting of side effects on health. However, medicines from natural products seem to be an alternative safety therapy approaches for AD treatment.\u00a0From this perspective, several studies using cell culture or animal\u2019s model have been conducted with promise to find news drugs from medicinal plants targeting A\u03b2 peptide and its subsequent pathophysiological effects.6\u00a0<\/sup>Almost of all valuable researches testing\u00a0pharmacological properties of medicinal plants extract against AD have used species originated from Asia.Paradoxically, African forests with a abundant and diversity of traditional use plants, scarce studies have so far focused the potential effects of their natural\u00a0products as anti-AD. In this setting, weplan to promote the effectiveness of african tropical area endemic specie as Chrysophyllum perpulchrum\u00a0<\/em>(Sapotaceae) by using of anAD-like rat model. It is used as antipyretic for cure malaria fever in Ivory coast traditional pharmacopeia,\u00a0and a provider of antioxidant source.7<\/sup><\/p>\n

Here, we tested whether methanolic bark extract of Chrysophyllum perpulchrum\u00a0<\/em>could have neuroprotective effects on memory deficits due to oxidative stress in a rat model of intracerebroventricular (i.c.v) A\u03b2 1-40<\/sub>injection-induced AD.<\/p>\n

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

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

The experiment was carried out using adult Wistar ratslocally obtained at the animals breeding house of Ibn Tofail University (Kenitra, Morocco). Animals were maintained for acclimation under controlled reference room at 22-25\u00b0C with a good relative humidity (50-60%), submitted to a 12 H light\/ dark cycle and have free access to standard food (ALF SAHEL Company of Casablanca) and tap water. All experimental protocols were carried out according to NIH guide for the care and use of laboratory animals and approved by local Ibn Tofail university local ethic committee.<\/p>\n

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

Chemicals of plant material<\/strong><\/p>\n

Bioactive compounds from Chrysophyllum perpulchrum\u00a0<\/em>termed Catechin (P1) and two dimeric procyanidins (P2 and P3)(Fig.1) were chromatographically isolated and tested for free radicals scavenging activity using2,2-diph\u00e9nyl-1-picrylhydrazyl,their activity is similar to quercetin.\u00a07,8<\/sup>The processes of methanolic, total phenolic contents or isolation compounds extractionhave been described elsewhere.7\u00a0<\/sup>Acute toxicity study estimated lethal dose 50 of Chrysophyllum perpulchrum<\/em> to 1250 mg\/kg of body weight (bw).8<\/sup><\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig1\"<\/a><\/td>\nFigure 1: Chemical structure of compoundsisolated from Chrysophyllum perpulchrum.<\/em><\/strong><\/p>\n

Click here to view figure\u00a0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

A\u03b2 preparation and treatments<\/strong><\/p>\n

Synthetic A\u03b21-40<\/sub> peptide (Sigma Aldrich, St. Louis, USA) were prepared as stock solution at concentration 1mg\/ml in 1% ammonia, and aliquots were stored at – 20\u00b0C. Before use, A\u03b21-40\u00a0<\/sub>solution was aggregated by incubation at 37\u00b0C for 4 days.9\u00a0For the stereotactic surgery, animals were prior anesthetized with chloral (300 mg\/Kg, i.p, in 7% solution) and were bilaterally i.c.v injectedwith A\u03b2at the lateral ventricle level ( coordinates Antero-poosterior= -0.8, Lateral = \u00b1 1.4, Dorso-ventral = -3.4)with a 10-\u00b5l Hamilton microsyringe.\u00a0\u00a0Animals were randomly divided into four experimental groupsof 6-7 animals each:(1)<\/strong>Shamgroup (10\u00b5l of 1% ammonia by i.c.v route), (2)A\u03b2group (10\u00b5g\/side of A\u03b2 1-40<\/sub>, i.cv route), (3)A\u03b2 + CPrats (10\u00b5g\/sidei.c.v route and treated with 300 mg\/kg of methanolic\u00a0bark extract of Chrysophyllum perpulchrum<\/em>), (4)Sham + CP (Sham operated rat and treated 300 mg\/kg of methanolic bark extract of Chrysophyllum perpulchrum<\/em>).<\/p>\n

The treatments with plant extract was done from 14th<\/sup> day post-surgery, a required period for A\u03b2 to cause neuroinflammation and oxidative stress.10, 11<\/sup><\/p>\n

Cognitive Testing<\/strong><\/p>\n

Y-maze<\/strong><\/p>\n

It was used to evaluate spatial working memory in rodent,12,13<\/sup>after all the treatments. The apparatus was made with in fine-wood with three arms (A, B and C) measuring 40 in length, 10cm in width and 13 cm in height) and painted in different colour patterns. A central\u00a0platform is formed by tri-angles of 120\u00b0 between each arm. The procedure consists to give 8 min-session to each rat for exploring freely the maze. The sequence of arms entrieswas monitored with a camera video. An entry was validated when the four paws are within the arms. Alternation is defined as a triad of successive entry in different arms (i.e<\/em>.\u00a0ABCACBAACB= 5 alternations). Spontaneous alternation behaviour was calculated with following equation: % alternation= 100 x (number of alternation\/ total arm entries \u2013 2).<\/p>\n

Recognition Memory Test (NORT)<\/strong><\/p>\n

The NORT is suitable to assess AD-related cognitive impairment.14<\/sup>The object recognition test procedure was conducted as describe by Ennaceur and Delacour.15<\/sup>The apparatus is an Open box with floor measurements 50 cm in length, 50 cm in width, and 40 cm in height walls. In\u00a0the trial (familiarization session), rats were allowed 5 min to explore freely the box with two identical objects and return in their home cage. After 2 h delay, to evaluate short term recognition Memory (STM), rats were return in open field in which one object was switched by another one different for colour, sharpe and size, and experiment was repeated during 5\u00a0min with one novel object and one identical previously explored.To evaluate long -term memory (LTM) 24h later from the familiarization phase, rats were submitted to explore again two objects for 5 min, one identical and another novel one.\u00a0 Objects and box were cleaned\u00a0with ethanol 70% during intertrial period. The exploration time of each object was recorded the video tracking, and the exploration feature is defined as the directing the nose at a distance less than 1 cm from the object. The ratio of preference of the novel object of each animal was\u00a0calculated from the exploration frequency of novel object divided the total frequency spent for exploring both objects.<\/p>\n

Morris Water Maze (MWM)<\/strong><\/p>\n

The MWM was performed to study spatial learning and memory. The apparatus was slightly modified of Morris Water maze test,16<\/sup> with circular open lightly grey pool (120 cm in diameter and 40 Cm in depth) filled with tepid water (22\u00b0C) at 30 Cm of width. It isdivided\u00a0into four virtual quadrants (North, South, West, and East) each including a visual cue outside the surface of water on the wall of the maze. In the habituation phase, animals were allowed 60 s to swim freely in the tank in order to define the best position of the platform which remained fixed during the all test sessions. Then, in the training phase, rats were left in the\u00a0tank facing the wall and then allowed to swim to find the hidden platform submerged to 1 cm to the surface of water. If the animal did not find the platform after 60 s elapsed, it was gently guided to it and stay for 15s before returning in home cage. The testing was completed in\u00a0fiveconsecutive days including four trials each. The behaviour of rat was recorded by a video camera placed on the ceiling above the maze.<\/p>\n

We considered the escape latency parameter as the time spent to find the platform.<\/p>\n

Oxidative stress level assay<\/strong><\/p>\n

After behavioural testing, rats were anesthetized with choral with (300mg\/kg) and killed by decapitation. Brain regions correspondent to Hippocampus and Prefrontal cortexareas were quickly removed and homogenized in ice-cold 50 mMTris-HCl buffer(pH 7.4). The homogenate was then centrifuged at 3000 rpm for 30 min at 4\u00b0C to obtain a supernatant that was used.<\/p>\n

Analysis of Non-protein Thiols (NP-SH) level<\/strong><\/p>\n

NP-SH level was assessed according to the method described by Ellman et al.<\/em>17<\/sup>The supernatant was treated with 10%of trichloroacetic acid to precipitate proteins, and the sample was centrifuged at 2.000 rpm for 10 min. To the supernatant, was added 1 M of potassium\u00a0 buffer (pH7.4) and 1mM of Ellman\u2019s reagent (5,5-dithiobis-2-nitrobenzoic acid). The NP-SHs levels were determined at 412 nm and expressed as \u00b5mol\/g of tissue.<\/p>\n

Determination of Lipid peroxidation level<\/strong><\/p>\n

The assay Malondialdehyde (MDA) level, an important index of lipid peroxidation, was described in the method of Satoh et al.<\/em>18<\/sup>Briefly, 500 \u00b5l of supernatant correspondent to sample of hippocampus or CPF was mixed with 1.5 ml of trichloroacetic acid (10%), vortexed\u00a0and incubated at room temperature for 10 min. Then it was added to the mixture 1,5 ml of thiobarbituric acid (0.67%), and heatedin boiling bath water for 15 min.After a cooling, 1.5 ml of n-butanol was mixed to the solution and strictly vortexed. The sample was centrifuged at\u00a0800 rpm for 5 min, and the supernatant was collected. The absorbance was determined spectrophotometrically at 532 nm. The results were expressed as MDA level nmol\/g of tissue.<\/p>\n

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

The experimental results data were expressed as means \u00b1 S.E.M (Standard Error of Mean). Statistical analysis were done using one-way analyses of variance followed by Tukey post-hoc test for multiple comparison, with value of p<0.05 considered statistically significant.<\/p>\n

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

Effects of Chrysophyllum perpulchrum extracton cognitive abilities in AD-<\/strong>like rats model induced by i.c.v A\u03b21-40<\/sub>injection\u00a0<\/strong><\/p>\n

Spatial working memory in Y-maze<\/strong><\/p>\n

Thei.c.v injection of A\u03b21-40<\/sub> caused an alteration of spatial working memory through a significant reduction of the percentageof spontaneous alternation behaviour (p<0.05), when compared to the performance of sham-operated rats and treated with 300mg\/kg of\u00a0Chrysophyllum perpulchrum<\/em> extract. However, even if, the treatment with 300 mg\/kg of Chrysophyllum perpulchrum<\/em> extract improved A\u03b21-40<\/sub>-induced working spatial memory impairment that was not significant (Fig.2).<\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig2\"<\/a><\/td>\nFigure 2: Chrysophyllum perpulchrum<\/em> extracteffect on spatial working memory ability in an AD-like rat\u2019s model. Sham (control rats as vehicle, i.c.vinjection with 10\u00b5l of 1% ammonia), A\u03b2 (i.c.v injectionA\u03b2 10\u00b5g by side ), A\u03b2+ CP (i.c.v injection of A\u03b2 (10\u00b5g\/side) and treated from 14th <\/sup>day post-surgery with 300 mg\/kg of Chrysophyllum perpulchrum<\/em>extract for 3 weeks),\u00a0<\/strong><\/p>\n

Click here to view figure\u00a0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Recognition memory in NORT<\/strong><\/p>\n

As indicated on the Fig. 3A, i.c. vinjection of A\u03b21-40<\/sub> impaired significantly STM recognition performance in A\u03b2 rats when compared to vehicle rats (p<0.01) and sham operated rats treated with 300 mg\/kg of crude extract (p<0.05). The treatment of AD-like rats during 3 weeks with\u00a0300 mg\/kg of crude extract of\u00a0Chrysophyllum perpulchrum<\/em>im proved the short-term recognition capacity as reflected by anincrease of the index.<\/p>\n

Regarding to the LTM recognition, the treatment with Chrysophyllum perpulchrum<\/em> extract prevented the impairments induced by A\u03b2i.c.v injection through a significant increase of recognition index above the threshold of 50% (p<0.05) (Fig.3 B).<\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig3\"<\/a><\/td>\nFigure 3:\u00a0Chrysophyllum perpulchrum\u00a0<\/em>extract effect on STM recognition (A) and LTM recognition (B)inan AD-like rat\u2019s model.<\/strong><\/p>\n

Click here to view figure\u00a0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Spatial learning and memory in MWM<\/strong><\/p>\n

We used MWM to assess spatial learning and memory which are hippocampal functions dependents. Our results showed that the experiment groups performed differently to locate the hidden platform in the maze (Fig.4). The i.c.v A\u03b2 injected rats learnt with difficulty to find the\u00a0platform during training day sessions, remarkably at day 1 (p<0.001), day 3 (p<0.01), day 4 (p<0.001), day 5 (p<0.001) compared to others groups. On the other hand, the treatment of i.c.v A\u03b2 rats with 300mg\/kg of plant extract over 3 weeks relieved significantly spatial\u00a0learning and memory deficit. Interestingly, the latency time to find the platform was shortened by the training day\u2019s sessions in the rats treated only with 300 mg\/kg of Chrysophyllum perpulchrum<\/em>crude extract.<\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig4\"<\/td>\nFigure 4:\u00a0Chrysophyllum perpulchrum <\/em>extract effect on spatial learning and memory abilities inan AD-like rat\u2019s model.Sham (control vehicle, i.c.v with 10\u00b5l of 1% ammonia)<\/strong><\/p>\n

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

Effects of Chrysophyllum perpulchrum extract on oxidative stress status in AD-like rats model induced by i.c.v A\u03b21-40 <\/sub>injection<\/strong><\/p>\n

Analysis of NP-SHs level<\/strong><\/p>\n

In prefrontal cortex, a significant decrease of NP-SH level was found in therats of A\u03b2 group (p<0.001)when compared to others ones. We noted that the A\u03b2 rats treated with 300 mg\/kg of crude extract of Chrysophyllum perpulchrum\u00a0<\/em>did not showed significant increase of NP-SH\u00a0level. However, the highest concentration of the NP-SH level was found in sham-operated rats treated with 300 mg\/kg of plant extract (Fig.5). The dosage of NP-SH in hippocampal area revealed the lowest level in A\u03b2 rats. However, the given treatment with\u00a0Chrysophyllum <\/em>perpulchrum\u00a0<\/em>extract to A\u03b2 rats caused significant increase of the level of NP-SH (p<0.01, A\u03b2 + CP vs A\u03b2 group). The same observation was done in the sham-operated rats treated with extract of Chrysophyllum perpulchrum<\/em> (Fig. 5).<\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig5\"<\/a><\/td>\nFigure 5:\u00a0Chrysophyllum perpulchrum <\/em>extract effect on NP-SH level in the prefrontal cortex and hippocampus of an AD-like rat\u2019s model.<\/strong><\/p>\n

Click here to view figure\u00a0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Analysis of MDA level<\/strong><\/p>\n

The i.c.v A\u03b2injection showed an increased level of lipid peroxidation which is reflected by high amount of MAD in both the prefrontal cortex and hippocampus(Fig.6). In the prefrontal cortex, there was very high significant increase of the MDA level in the A\u03b2 rats group\u00a0 (p<0.001). The treatment with Chrysophyllum perpulchrum<\/em> extract help to counteract the lipid peroxidation observed in A\u03b2 rats. At the same manner, in hippocampus, there was high significant raising of MDA concentration in A\u03b2 rats group (p<0.001), while the treatment with bark crude extract of Chrysophyllum perpulchrum\u00a0<\/em>avoided high level of lipid peroxidation. The sham-operated rats with plant extract treatment were not significantly affected compared to A\u03b2 rats with plant treatment (p<0.05).<\/p>\n\n\n\n
\"Vol14No3_Cog_Pac_fig6\"<\/a><\/td>\nFigure 6: Chrysophyllum perpulchrum <\/em>extract effect on lipid peroxidationin the prefrontal cortex and hippocampus of an AD-like rat\u2019s model.<\/strong><\/p>\n

Click here to view figure\u00a0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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

The increase of risk factors of AD sporadic form could rise the prevalence in SSA population during upcoming years. Thus, as none drug is yet efficient against AD, it becomes now worthwhile to conduct further experiments with goal to find drugs based on natural products\u00a0from African\u2019s endemic medicinal plants. To our knowledge, there is no yet researches\u00a0 having studied pharmacologically and clinically the beneficial effects of any Ivoirian\u2019s medicinal plants in the neurodegenerative diseases context. The present study is a first one launched to\u00a0evaluate whether methanolic extract of Chrysophyllum perpulchrum <\/em>could relieve memory and cognitive deficits, and alleviate oxidative stress status in an AD-like rats induced by i.c.v A\u03b21-40 <\/sub>injection. We found as main findings significant deficits of short-term and long-term object\u00a0recognition, and spatiallearning and memoryabilities in A\u03b2 rats. However, the treatment of AD-like rats with crude extract of\u00a0Chrysophyllum perpulchrum\u00a0<\/em>rescued cognitive impairments.Interestingly, AD-like rats treated with plant extract performed\u00a0some times behavioral tests at the same manner as the rats of control or sham operated-treated with plant extract groups. Also, the treatment by Chrysophyllum perpulchrum<\/em> extract prevents oxidative stress and lipid peroxidation in hippocampus or prefrontal cortex observed in AD-\u00a0like rats. Here, we discuss our results with others possible actions supposed to be due to bioactive compounds from\u00a0 Chrysophyllum perpulchrum<\/em> against AD.<\/p>\n

It has been reported that object recognition task is a suitable behavioral test to evaluate AD-related cognitive impairments as well as hippocampus-dependent spatial learning and memory assessed with MWM.14\u00a0<\/sup>Poor performances of i.c.v A\u03b2 rats compared to others in\u00a0behavioral testing arise the question to know the chronology events occurred in the physiopathology mechanisms according to our experimental procedure.Firstly, we suggest that the target of one bio active component of Chrysophyllum perpulchrum\u00a0<\/em>namely catech in is\u00a0AChE inhibitor. In fact, AChE is largely recognised to promote acceleration of A\u03b2 sheet polymerization, fibrillization and its aggregation in amyloid plaque.19,<\/strong>20<\/sup><\/p>\n

A previous study mentioned that polyphenolic compounds are well known to inhibit AChE which is a key enzyme in AD.21<\/sup>More specifically, Olasehende et al<\/em>22\u00a0<\/sup>when testing the anti-amyloidogenic effects of Catech in and derived compounds isolated from seaweeds, have\u00a0in vitro<\/em> highlighted a significant reduction of aggregated A\u03b21-42\u00a0<\/sub>level. Another experiment using\u00a0in vivo<\/em> mice\u2019s model of AD confirmed that catechin from Rhizophora mucronata<\/em> enhanced cognitive functions by inhibiting AChE and others cholinesterases.23\u00a0<\/sup>The neuroprotective effects of Chrysophyllum perpulchrum<\/em> extract on memory performances suggest partly to\u00a0be related to its effect on A\u03b2 clearance. It is clearly established that A\u03b2 mediates oxidative stress by different processes leading to production of ROS like super oxide anion radical, hydrogen peroxide or hydroxyl radical among others.24\u00a0<\/sup>Oxidative stress occurred when the\u00a0level of free radicals generated by A\u03b2 exceeds the cells natural antioxidants including glutathione and antioxidant enzymes as superoxide dismutase, catalase and glutathione peroxidase. Oxidative stress in brain is a major factor that underlies neurotoxicity in the AD,\u00a0\u00a0with consequence of cells damage or death by apoptosis.25\u00a0<\/sup>An approach of supplementation with exogenous antioxidants from natural substance may be effective to prevent A\u03b2-induced toxicity or halt AD progression.26\u00a0<\/sup>In our study, there was an increased of\u00a0NP-SH level (90% represented by gluthation) in hippocampus of A\u03b2 rats after treatment with\u00a0Chrysophyllum perpulchrum\u00a0<\/em>extract, when compared to A\u03b2 rats without treatment. However, we found that this difference was less observed in the prefrontal cortex. Our results\u00a0are in agreement with previous study that showed significant increase in glutathione in a rat\u2019s model of AD treated with natural antioxidant plant Cantella asiatica<\/em>.27\u00a0<\/sup>In fact, it has been demonstrated that A\u03b2 is able to cause high-depleted level of glutathione in brain and reduce synaptic density.28<\/sup><\/p>\n

It plays neuroprotective role from oxidative stress by reacting with prooxidant hydroxyl peroxide to give rise to the oxidized form of glutathione. We can suggest that active compounds of Chrysophyllum perpulchrum<\/em> extract help to combate A\u03b21-40<\/sub>-induced oxidative\u00a0stress by enhancing NP-SH level.In another way, high concentration of NP-SH in hippocampus is thought to be linking to its great vulnerability to oxidative stress,29<\/sup>it is the primary brain site affected in AD condition before extending toward the cerebral cortex for\u00a0advanced cognitive disorders.Healthy brain contains much macromolecules which are susceptible to oxidative stress. One of subsequent effects of A\u03b2-facilitated extensive oxidative stress is peroxidation of membrane lipids, leading to neuronal damage and death by apoptosis.25\u00a0<\/sup>It has been clearly found a positive correlation between A\u03b2 plaques and lipid\u00a0peroxidation in AD brain.30\u00a0<\/sup>Our experiment highlighted high level of MDA in hippocampus and prefrontal cortex in A\u03b2 rats, certainly due to high lipid peroxidation of neuronal membranes.However, the treatment with Chrysophyllum perpulchrum<\/em> extract attenuated A\u03b21-40<\/sub>-induced membrane lipid peroxidation. A significant lessening of MDA level was observed\u00a0in brain ofA\u03b2 rats treated with plant crude extract. Similar results were reported by Schimidt et al<\/em>31<\/sup>which sustain that catechin from Camellia sinensis<\/em> avoids lipid peroxidation in AD rat model, and relieves oxidative stress and memory deficits. Another key toxicity action of A\u03b2\u00a0isbased on its high affinity toward redox-active metalcopper or iron which releases hydrogen peroxide and hydroxyl and responsible for membrane lipid peroxidation.32<\/sup><\/p>\n

The supplementation of catechin contained in Chrysophyllum perpulchrum<\/em>\u00a0 extract could be considered as potent redox metal-chelator for the prevention membrane peroxidation and cognitive disorders related to AD. Otherwise, oxidative stress condition promotes progressively the neuronal loss mainly by apoptotic pathway.33<\/sup> In this sense, a\u00a0previous study investigating the beneficial effects of Catechin-rich from methanolic extract of\u00a0Rhuzophora mucronata\u00a0<\/em>demonstrated aninhibition of hippocampal neurons apoptosis by down\u2013regulating caspase 3 in a mice model of i.c.v administration of aggregated A\u03b2.23<\/sup><\/p>\n

We remind that Chrysophyllum perpulchrum<\/em> extract contains two dimeric procyanidin compounds.[7]<\/sup> An important factor suggested to prevent A\u03b2-induced cognitive deficits is probably the neuroprotective effects of procyanid in. For this purpose, procyanid in\u00a0B1 from a medicinal plant (Uncaria hook<\/em>) suppressed actively A\u03b2 oligomeric-induced neurotoxicity, their neuroprotective action consists so to attenuate activation of Caspase 3 by inhibiting the pro-caspase 8 or 9.34<\/sup> All results regarding\u00a0Chrysophyllum perpulchrum<\/em> or others\u00a0plant species mentioned rich in catechin and procyanidin suggest that this should be proposed asphytotherapeutic drug for AD because of their antioxidante, anti-apoptosis, and likewise their anti-AChE properties.<\/p>\n

Although we found some neuro protection effects of crude extract of Chrysophyllum perpulchrum sp<\/em>on memory and cognitive performances in i.c.v injected A\u03b2 rats, we cannot exclude the possibles mechanisms of A\u03b2 clearance from lateral ventricle in order to\u00a0validateour experimental model. The processes of A\u03b2 influx or efflux beetwen brain parachyma and blood-cerebrospinal fluid via brain barriers remains poorly understood as well as the threshold amount of A\u03b2 level to provoke AD. It has been experimented in mice\u2019s model of\u00a0AD that the efflux of A\u03b2 from central nervous to plasma increasing the blood baseline level 200 pg\/mL to 5-10 ng\/mL ((0.5-1).10-2<\/sup> \u00b5g\/\u00b5l) within 24 h.35<\/sup> That suggest that the burden of i.c.v A\u03b2 injected in our experiment (10\u00b5g of A\u03b2\/side) could be sufficient to extend half-life\u00a0avoiding so a faster A\u03b2 clearance. However, some authors conclude their experiment in vitro<\/em> by suggesting that choroid plexus of CSF reduces potentially A\u03b2 from normal brain or AD brain because that area contains potent mechanism of A\u03b2 efflux via lipoprote in receptor-related protein,36\u00a0<\/sup>as also early demonstrated in vivo.37\u00a0<\/sup>Another limit is the effectiveness of therapeutic concentration of bioactive compounds catech in and procyanidins contained in the dose of Chrysophyllum perpulchrum\u00a0<\/em>(300mg\/kg for 21 days)used in our experiment. Even if\u00a0\u00a0we found positive cognitive and antioxidant outcomes with our medicinal plant, some pharmachokinetic properties including bio availibilty and excretion must be take account. In fact, none study regarding catech in or procynad in from Chrysophyllum perpulchrum\u00a0<\/em>has been\u00a0addressed in this sense, but a past report revealed for instance that by oral route catech in from green tea reached a blood peak 1-2 hours followed by an elimination by 5-6 hours.38\u00a0<\/sup>Those authors suggested that an administration every 4 h should allow to maintain high blood level of catech in.It could be interesting to investigate using larger or lower concentration, and duration of treatment in order to further appreciate the dose and time-dependant effects.<\/p>\n

Conclusions<\/strong><\/p>\n

The present study is a first to promote neuroprotective actions of ivorian\u2019s traditional plant\u00a0Chrysophyllum perpulchrumsp\u00a0<\/em>using AD-like rat model induced by i.c.v A\u03b2 injection.We can predict that the bioactive compounds catechin and dimer procyanidins (catechin + Hexose) act to attenuate oxidative stress status and relieve memory deficits in the AD condition. However, the challenge remains to tackle its full pharmacological targets.<\/p>\n

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

We thank IBRO ARC committee which supporting travel and stay grant at the Cajal Institute (Madrid) for stereotaxic method training.<\/p>\n

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

No conflict of interest\u00a0was reported by authors<\/p>\n

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

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