|Year : 2014 | Volume
| Issue : 4 | Page : 204-209
Preliminary histological and histochemical studies on the neuroprotective effect of aqueous fruit extract of phoenix dactylifera L. (Date Palm) on atesunate - induced cerebellar damage in wistar rats
Abel Nosereme Agbon, Sechivir Damilola Ingbian, Ahmadu Usman Dahiru
Department of Human Anatomy, Faculty of Medicine, Ahmadu Bello University, Zaria, Nigeria
|Date of Submission||14-Mar-2014|
|Date of Acceptance||21-Jul-2014|
|Date of Web Publication||14-Nov-2014|
Abel Nosereme Agbon
Department of Human Anatomy, Faculty of Medicine, Ahmadu Bello University, Zaria
Context: The cerebellum is vulnerable to damage from a variety of sources such as degenerative diseases, infectious processes and toxins, like antimalarial drugs. Various parts of Phoenix dactylifera (date palm) are used in traditional medicine to treat various disorders such as memory disturbances, loss of consciousness, nervous disorders, etc., in different parts of the world. Aim: The neuroprotective effect of aqueous fruit extract of P. dactylifera (AFPD) was assessed against artesunate (AS) (antimalarial drug) - induced cerebellar damage in Wistar rats. Materials and Methods: Twenty Wistar rats (male and female) were divided into five groups (A-E) of four rats each. Group A was the control whereas Groups B-E were treatment groups. Cerebellar toxicity was experimentally induced in Wistar rats by administering AS. Group B was administered AS (300 mg/kg, oral). Groups C, D, and E were administered AFPD (500 mg/kg, 1000 mg/kg and 1500 mg/kg, oral, respectively) followed by AS (300 mg/kg, oral) for a period of 7 days. Neuroprotective activity was studied by histopathological examination of brain sections applying routine (Haematoxylin and Eosin) and histochemical (Cresly Fast Violet) staining techniques. Statistical Analysis Used: One-way analysis of variance. Results: Histopathological examination of brain sections revealed neuronal degeneration of cerebellar cells, such as, vacuolations and degeneration of Purkinje cells, and alteration in the general histoarchitecture of cerebellum was observed in AS-intoxicated group. The administration of AFPD remarkably inhibited AS-induced neuronal damage in Wistar rats with maximum neuroprotective effect at 500 mg/kg and 1500 mg/kg doses when compared with tissue sections of AS-intoxicated group. Conclusion: Result suggests that the effectiveness of AFPD in neuroprotection is probably due to its constituent antioxidant properties.
Keywords: Artesunate, cerebellar toxicity, histochemistry, histology, neuroprotection, phoenix dactylifera
|How to cite this article:|
Agbon AN, Ingbian SD, Dahiru AU. Preliminary histological and histochemical studies on the neuroprotective effect of aqueous fruit extract of phoenix dactylifera L. (Date Palm) on atesunate - induced cerebellar damage in wistar rats. Sub-Saharan Afr J Med 2014;1:204-9
|How to cite this URL:|
Agbon AN, Ingbian SD, Dahiru AU. Preliminary histological and histochemical studies on the neuroprotective effect of aqueous fruit extract of phoenix dactylifera L. (Date Palm) on atesunate - induced cerebellar damage in wistar rats. Sub-Saharan Afr J Med [serial online] 2014 [cited 2020 May 28];1:204-9. Available from: http://www.ssajm.org/text.asp?2014/1/4/204/144744
| Introduction|| |
The cerebellum is part of the brain responsible for motor movements, coordination, balance, equilibrium and muscle tone.  Microscopically, the cerebellum consists of three distinct layers: The outermost molecular layer which contains few nerve cells; the inner granular layer that consists of densely packed granule cells and the middle Purkinje cell layer that contains a monolayer of Purkinje cells sandwiched between the molecular and granular layers. , The cerebellum is vulnerable to damage from a variety of sources such as developmental defects, degenerative diseases, infectious processes, chronic alcoholism, trauma and tumors.  Cerebellar injuries have been reported to result from toxins, such as, antimalarial drugs. ,
Artesunate (AS), a member of artemisinin derivatives, is an antimalarial drug commonly used in chloroquine resistant cases of plasmodum falciparum infection. , The parent compound, artemisinin, is the antimalarial principle of this compound and is derived from the leaves of a Chinese plant called Artemisia annua (sweet wormwood) which has been successfully used to treat malaria associated fevers since 138 BC. , AS is a rapidly acting drug, and its effectiveness has been attributed to its rapid and extensive hydrolysis to dihydroartemisinin which is three to five-folds more active and more toxic, than the parent compound. , Clinical studies conducted, mainly, in Africa and Asia, have identified a favorable tolerability profile for artemisinin derived drugs, however, many patients have experienced adverse neurological effects.  Artemisinin derivatives are potent antimalarial drugs, but concern has been raised as to their neurotoxic potential.  AS has been reported to cause gait disturbances, loss of spinal cord and pain response mechanisms in animals. , Several studies have shown that high doses of AS can produce neurotoxicity such as selective damage to brain stem centers in mice and rats. 
Plant material in the human diet contain a large number of natural compounds with a wide range of medicinal actions, and throughout history, they have been used to treat many different types of diseases. More recently, however, scientists have begun investigating the biological activities of medicinal plants, including their neuroprotective actions. ,
Phoenix dactilyfera L. (date palm) belongs to the family Arecaceae.  It is believed to be indigenous to the countries around the Persian Gulf.  Phoenix dactylifera fruits are an important component of the diet in the arid and semiarid regions of the world  and are a good source of energy, Vitamins, and a group of elements like phosphorus, iron, potassium, and a significant amount of calcium. , Dates contain at least six Vitamins including a small amount of Vitamin C, and Vitamins B 1 (thiamine), B 2 (riboflavin), nicotinic acid (niacin) and Vitamin A.  Different parts of the plant are traditionally claimed to be used for the treatment of a broad spectrum of ailments including memory disturbances, fever, inflammation, paralysis, loss of consciousness and nervous disorders.  It has been scientifically reported to possess a variety of pharmacological activities, such as, antiulcer, hepatoprotective, antimutagenic, antidiarrhoeal, antiinflammatory and antioxidant activities. ,,,,
The aim of this study was to histologically and histochemically assess the neuroprotective effect of aqueous fruit extract of P. dactylifera (AFPD) against AS-induced cerebellar toxicity in Wistar rats.
| Materials and methods|| |
Date palm (P. dactylifera) fruits were obtained from Samaru market in Zaria, Kaduna, Nigeria. Authenticated and deposited in the Herbarium unit of the Department of Biological Sciences, Faculty of Sciences, Ahmadu Bello University, Zaria, Kaduna State, Nigeria with the Voucher Specimen Number of 7130.
Extraction of P. dactylifera fruit was conducted in the Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Kaduna, Nigeria. The method of maceration as reported by Agbon et al.  for the preparation of AFPD was adopted.
Experimental animals (Wistar rats) weighing between 150 and 200 g were obtained from Pharmacology Animal House Center, Faculty of Pharmaceutical sciences, Ahmadu Bello University, Zaria, Kaduna, Nigeria, were housed in wired cages in the animal house of the Department of Human Anatomy, Faculty of Medicine, Ahmadu Bello University, Zaria, and were acclimatized for 2 weeks prior to the commencement of the experiments. The animals were housed under standard laboratory condition, light and dark cycles of 12 h, and were provided with standard rodent pellet diet and water ad libitum. The rats were categorized into control and treatment groups. The treatment groups were administered, in addition to feed and water, AFPD and/or AS for a period of 1-week. The rats and their organs (brain) were weighed at the end of the study and organ (brain)/body weight ratio computed.
Artesunate (Adams Pharmaceutical [ANHUI], CO., Limited).
Twenty (20) Wistar rats (male and female) were divided into five groups (A-E) of four rats each. Group A served as control administered distilled water (0.5 ml) while, Groups B, C, D and E were treatment groups. Cerebellar neurotoxicity was induced in rats by the administration of AS at dose of 300 mg/kg which is about 30% of the drug's LD 50 (980 mg/kg, oral) in rats.  Group B was administered AS (300 mg/kg, oral) only. Groups C, D and E were administered AFPD (500 mg/kg, 1000 mg/kg and 1500 mg/kg, oral, respectively), followed by AS (300 mg/kg, oral) for a period of the week.
All the rats were humanely sacrificed under chloroform anesthesia and brain organs harvested, fixed in Bouin's fluid for routine histological tissue processing and stained with Hematoxylin and Eosin and histochemical (Cresly Fast Violet) stains, and examined under a light microscope.
Results obtained were analyzed using the statistical software, GraphPad Prism version 4.03 (GraphPad Software, Inc. 7825 Fay Avenue, Suite 230, La Jolla, CA 92037, USA) for Windows. The data were expressed as mean ± standard error of mean brain/body weight ratios between the groups were compared using one-way analysis of variance, followed by Dunnett's multiple comparison post-hoc test. Values of P < 0.05 were considered significant.
| Results|| |
Wistar rats in the control group showed normal physical activities such as movement and playfulness, whereas animals in the treatment groups exhibited decreased activity, especially in AS-treated group (Group B).
There was marked decrease (P < 0.05) in the organ (brain)/body ratio in the AS treated group when compared with the control [Table 1].
|Table 1: Brain/body weight ratio of Wistar rats treated with aqueous fruit extract of P. dactylifera against artesunate– induced neurotoxicity|
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Histological examination of tissue sections of the cerebellum revealed the following : t0 he cerebellar sections of animals in the control group showed normal histoarchitecture of the cerebellar cortex; the characteristic appearance of the three cortical layers : a0 n outer molecular layer with distinct neurons and an inner granular layer. Sandwiched between these layers is a monolayer of flask-shaped Purkinje cells, the Purkinje cell layer. Histochemical (Cresly Fast Violet) staining for Nissl substances revealed normal appearance of distinct intensely stained cortical neurons [Figure 1]a and b.
|Figure 1: Micrograph of cerebellum of Wistar rat Haematoxylin and Eosin stain (a, c, e, g and i), and Cresyl Fast Voilet stain (b, d, f, h and j) (×250). (a and b) Section of cerebellum of the control group showing normal histoarchitecture. G = Granular layer, M = Molecular layer; P = Purkinje cell. (c and d) Section of the cerebellum of group administered artesunate (AS) (300 mg/kg) showing histoarchitectural distortion. D = Disintegrated nerve cells and fi bers, G = Granular layer, M = Molecular layer, N = Neuronal degeneration, P = Purkinje cell. (e and f) Section of the cerebellum of group administered AS (300 mg/kg) and aqueous fruit extract of Phoenix dactylifera (AFPD) (500 mg/kg) showing mild histoarchitectural distortion. G = Granular layer, M = Molecular layer. (g and h) Section of the cerebellum of group administered AS (300 mg/kg) and AFPD (1000 mg/kg) showing mild histoarchitectural distortion. G = Granular layer, M = Molecular layer. (i and j) Section of the cerebellum of group administered AS (300 mg/kg) and AFPD (1500 mg/kg) showing mild histoarchitectural distortion. G = Granular layer, M = Molecular layer, P = Purkinje cell|
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The cerebellar sections of animals treated with AS revealed distortion in the histoarchitecture of the cerebellar cortex; cortical degenerative changes and vacuolations. The granular layer showed neuronal degeneration, and Purkinje cell layer showed loss and degeneration of Purkinje cells which appeared as vacuolations and smaller sized Purkinge cells. Infiltration of inflammatory cells was also observed. Staining for Nissl substances showed degenerative changes; indistinct neurons, as a result, of reduced staining intensity, compared to the control [Figure 1]c and d.
The cerebellar sections of animals treated with AFPD at all doses (500 mg/kg, 1000 mg/kg and 1500 mg/kg) followed by the administration of AS (300 mg/kg) revealed mild distortion of the histoarchitecture of the cerebellar cortex, such as necrotized cells in the molecular layer, when compared with the severe histoarchitectural distortion observed in the AS treated group. Histochemical staining with Cresly Fast Violet showed distinct and intensely stained cortical neurons, which manifested best in groups pretreated with 500 mg/kg and 1500 mg/kg extract [Figure 1]e-j.
| Discussion|| |
Decreased physical activity exhibited by AS treated Wistar rats reflects treatment-related toxicity. This is in concordance with reports on drug-related toxicity; altered physical activity manifesting as sluggishness and loss of appetite indicates drug-related toxicity. ,
Body weight changes serve as a sensitive indication of the general health status of animal,  and used as an indicator of adverse effect of drugs and chemicals.  Marked (P < 0.05) decrease in the organ (brain)/body ratio observed in the AS treated group when compared to the control indicates treatment-related toxicity.
Histoarchitectural distortion of neural tissue manifesting as, neuronal degenerative changes are indicative of neurotoxicity in the central nervous system. ,, Degenerative changes observed as, cortical neuronal degeneration and vacuolations and loss of cellular components with reduced population of Purkinje cells in cerebellar section of rats treated with AS when compared with the cerebellar section of control implies treatment (AS) related neurotoxicity. This is in concordance to previous studies on AS administration; high doses of AS can produce neurotoxicity in mice and rats. ,,,, AS crosses membrane and affects the cellular integrity of tissue. In this study, AS possibly acted as a neurotoxin to the cerebellar cortex, as such, distorting neuronal integrity and causing disruption in membrane permeability and tissue homeostasis. The degenerative effect of AS on the cortical layers of the cerebellum observed in this study may be responsible for the cerebellar degeneration. 
Cells death has been reported to result from neuronal degeneration.  Cell death may result from necrosis, a pathologic type of cell death that occurs from extrinsic insults to the cells or after abnormal stresses, such as chemical injury or toxin, thermal, traumatic and mechanical factors. ,, Mild histoarchitectural distortion, such as necrosis, observed from cerebellar sections of animals treated with AFPD followed by the administration of AS is indicative of AS-induced neurotoxicity; necrosis is an indication of treatment-related toxicity. 
Adverse effects, at therapeutic doses, with artemisinin derivatives when administered alone or in combination with other antimalarials have been clinically reported. Adverse neurological effects after treatment include acute psychosis, depressant syndrome, sleep disturbance  and postcerebellar syndrome-ataxia and slurred speech.  It is not impossible that AS had irreversible neurotoxic effect on the cortical layer of the cerebellum, which resulted in distortion, loss of the cellular component and Purkinje cells in the cortical layers of the treated cerebellar section. 
Rough endoplasmic reticulum and free ribosomes appear under a light microscope as basophilic granular areas called Nissl bodies with Cresy Fast Violet staining. Neuronal degeneration has been reported to cause a reduction in Nissl boches.  The observed neuronal degeneration : l0 oss of Nissl bodies with consequent reduced staining intensity of the Nissl substances in the cerebellar section of the AS-treated Wistar rats in this study is in concordance with reports by the earlier findings of Classen et al.  reporting loss of Nissl substance in neurons and shrinkage of the nucleus, which became prominent in the cerebellar roof, pontine and vestibular nuclei of dog following intramuscular administration of artemether. Loss of Nissl substance observed in this study is also consistent with reports of Ajibade et al. ,
Pretreatment of Wistar rats with AFPD at all doses (500 mg/kg, 1000 mg/kg and 1500 mg/kg) showed preserved histoarchitecture of the cerebellar cortex parenchyma and cytoarchitectural preservation of neuronal cell Nissl substance. This implies that, the extract has a protective effect against AS-induced neurotoxicity. Results from this study are in consistence with reports on the neuroprotective effect of P. dactylifera extract. , Kalantaripour et al.  reported that, extract of P. dactylifera protected cortical neurons against ischemia-reperfusion induced insults in Wistar rats.
Antioxidant effects have been implicated for neuroprotective activity of P. dactylifera. ,,, Some of known neuroprotective agents of AFPD are melatonin, a potent antioxidant and free radical scavenger with special tendency to brain, , Phenolic compounds consist of cinnamic acids and different flavonoids with strong antioxidant properties, ,,, Vitamin C, a known antioxidant compound,  Magnesium, an antagonist of N-methyl-D-aspartate receptors,  Vitamin B 3 , a water-soluble Vitamin with neuroprotecive property, , manganese, a free radical scavenger,  selenium, an antioxidant agent with synergic effect with Vitamin C.  Considering the existence of the different compounds, AFPD is a unique natural complex neuroprotective agent. 
In this study, maximum protective effects of AFPD were observed with doses 500 mg/kg and 1500 mg/kg, and lower protective effects with dose 1000 mg/kg. This is consistent with the findings reported by Majid et al.;  AFPD with dose of 1000 mg/kg showed negative effect on the rate of neuronal death in CA1 hippocampus following focal cerebral ischemia, which may be due to high concentration of antioxidants that may be harmful.  However, findings from this study is in converse to the findings of Majid et al.,  that reported lower protective effect of AFPD with 500 mg/kg and negative effect due to the high concentration of antioxidants from high dose, as maximum protective effects was observed with 1500 mg/kg dose. This suggests that, the neuroprotective effect of AFPD may involve different mechanisms of constituent antioxidant activities. The protective mechanisms are not known precisely, but the synergic effect of various antioxidative constituents of AFPD may explain its neuroprotective mechanism. 
| Conclusion|| |
The present study demonstrated that AFPD histologically and histochemically protected the cortical cerebellar neurons against AS-induced cerebellar neurotoxicity in Wistar rats with maximum neuroprotective effect at 500 mg/kg and 1500 mg/kg doses. Possible neuroprotective activity of the plant extract may be resultant to the antioxidant activities of constituent phytochemicals. This is suggestive of the unique and usefulness of date fruit, thus, its regular consumption may be helpful for health.
| Acknowledgment|| |
We wish to acknowledge Mr. A. A. Bamidele for technical support and the Department of Human Anatomy, Faculty of Medicine, Ahmadu Bello University, Zaria for providing the facilities to conduct this study.
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