INTRODUCTION:

Sickle cell anemia is a disease passed down through families in which red blood cells form an abnormal crescent shape. (Red blood cells are normally shaped like a disc.)Myths fuelled by cultural beliefs are issues to contend with. For example, childhood deaths within a family were always attributed to some evil forces in the traditional African setting. The advent of Western medicine changed all that when the real causes of many of such deaths became apparent. In different parts of the world especially in Africa and Asia with high incidence of the sickle cell disease, the people have learnt to manage the problem using plants which are God’s gift of nature. Crude extracts from plants have been used in treating an array of diseases since ancient times although, the bioactive components of such plants remain largely unknown. Various advances in scientific research on the use of plants and herbs brought the beneficial aspects of traditional medicine and the rational for their uses to the limelight. This review seeks to spotlight the intervention of medicinal plants in the management of Sickle Cell Disease (SCD) by traditional healers and the underlying principles in their usage.¹ Anti sickling effects of different substances have been investigated.

Dried fish (Tilapia) and dried prawns (Astacus red) extracts were established to have the ability to inhibit polymerization of sickle cell hemoglobin (HbS), improve the Fe2+/Fe3+ status and lower the activity of lactate dehydrogenase (LDH) in the blood plasma. LDH is a sensitive indicator of hemolysis and its level in sickle cell blood, determines the severity of crises. There have also been reports on effective management of SCD patients during pregnancy.^2,3

Causes, incidence, and risk factors:

Sickle cell anemia is caused by an abnormal type of hemoglobin called hemoglobin S. Hemoglobin is a protein inside red blood cells that carries oxygen. Hemoglobin S changes the shape of red blood cells, especially when the cells are exposed to low oxygen levels. The red blood cells become shaped like crescents or sickles. The fragile, sickle-shaped cells deliver less oxygen to the body's tissues. They can also get stuck more easily in small blood vessels, and break into pieces that interrupt healthy blood flow.⁴Sickle cell anemia is inherited from both parents. If you inherit the hemoglobin S gene from one parent and normal hemoglobin (A) from your other parent, you will have sickle cell trait. People with sickle cell trait do not have the symptoms of sickle cell anemia. Sickle cell disease is much more common in people of African and Mediterranean descent. It is also seen in people from South and Central America, the Caribbean, and the Middle East.⁵

Symptoms:⁶

Symptoms usually don't occur until after age 4 months.

Common symptoms include:

· Attacks of abdominal pain

· Bone pain

· Breathlessness

· Delayed growth and puberty

· Fatigue

· Fever

· Rapid heart rate

· Ulcers on the lower legs (in adolescents and adults)

Signs and tests:⁶

Tests commonly performed to diagnose and monitor patients with sickle cell anemia include:

· Complete blood count (CBC)

· Hemoglobin electrophoresis

· Sickle cell test

Treatment:

The goal of treatment is to manage and control symptoms, and to limit the number of crises.⁷

Treatment for a sickle cell crisis includes:

· Blood transfusions (may also be given regularly to prevent stroke)

· Pain medicines

· Plenty of fluids

Complications:

· Acute chest syndrome

· Anaemia

· Blindness/vision impairment

· Brain and nervous system (neurologic) symptoms and stroke

· Death

· Disease of many body systems (kidney, liver, lung)

· Drug (narcotic) abuse

Prevention:

Sickle cell anemia can only occur when two people who carry sickle cell trait have a child together. Genetic counseling is recommended for all carriers of sickle cell trait. About 1 in 12 African Americans has sickle cell trait.⁸

If you have sickle cell anemia, you can prevent the change in red blood cell shape by:

· Getting enough fluids

· Getting enough oxygen

· Quickly treating infections

History:

Sickle Cell Disease in African Tradition:

Sickle cell disease has been known to the peoples of Africa for hundreds of years.^[9] In West Africa various ethnic groups gave the condition different names:

Sickle Cell Disease in the Western Literature:

Description of Sickle Cell Disease:

In the western literature, the first description of sickle cell disease was by a Chicago physician, James B. Herrick, who noted in 1910 that a patient of his from the West Indies had an anemia characterized by unusual red cells that were "sickle shaped."

Relationship of Red Cell Sickling to Oxygen:

In 1927, Hahn and Gillespie showed that sickling of the red cells was related to low oxygen.¹⁰

Deoxygenation and Hemoglobin:

In 1940, Sherman (a student at Johns Hopkins Medical School) noted a birefingence of deoxygenated red cells, suggesting that low oxygen altered the structure of the hemoglobin in the molecule.¹¹

The Problem:

Sickle cell disease is caused by the substitution of glutamic acid with valine at the sixth position of the beta-globin chain of hemoglobin S (HbS) and different amino-acids can be substituted at the same time. The variants of sickle cell disease include those that produce prominent clinical manifestations as seen in sickle cell anemia HbSS, sickle cell HbC disease, sickle cell α-thalassemia, while sickle cell trait (HbAS), which has never been considered a disease, has one abnormal gene.¹² The deficiency caused by abnormal hemoglobin like HbS, HbC, Hb α-thalassemia and glucose-6-phosphate are now known. Under hypoxic conditions, deoxy-HbS molecules polymerise, forming rigid, sickled cells. This in turn causes the deformation of the normal disc biconcave RBC. Due to polymerization of the sickled cells, the red cell membrane loses its functional abilities which results in loss of K+ and water and a corresponding gain of Na+. Increased intracellular free Ca2+ occurs during sickling, resulting in a loss of K+ with accompanying movements of Cl- and water.¹³ Small blood vessels are blocked by the clumping of sickled RBCs, preventing blood supply to various organs. Deoxygenation in tissue capillaries causes damage to its endothelium, leading to exudation of plasma into the surrounding soft tissue. This is characteristic of the soft tissue swelling seen in most sickle cell disease patients.¹³

Clinical Manifestations:

The phenotypic expression of sickle cell anemia varies greatly among patients and longitudinally in the same patients. Clinical manifestations of sickle cell disease are diverse and varied and fall into three major categories: anemia, pain related issues and organ failure. Blocked blood vessels and damaged organs can cause acute painful episodes or “crises”. Sickle cell crises may be caused by blood vessel occlusion, triggered by membrane deformation. SCD patients suffer from a variety of ailments which includes acute chest syndrome (ACS) which is one of the reasons for hospital admissions, stroke, and acute splenic sequestration. Other clinical manifestations of this condition are hyposthenuria, priapism, vascular necrosis, proliferative retinopathy, aplastic crises, cholelithiasis, delayed growth and sexual maturation, chronic pulmonary disease and chronic nephropathy.¹⁴

TABLE: 1 List of herbal plants used in the treatment of sickle cell anaemia

S.NO	Biological source	Part used	Therapeutic Action
1.	Piper guineensis	Seeds	Antisickling Activity
2.	Pterocarpa osun	Stem	Antisickling Activity
3.	Eugenia caryophyllala	Fruit	Antisickling Activity
4.	Sorghum bicolor	Leaves	Antisickling Activity
5.	Pterocarpus santolinoides	Extract	Increase the gelling time of sickle cell blood and inhibits sickling in vitro.
6.	Aloe vera	Extract	Increase the gelling time of sickle cell blood and inhibits sickling in vitro.
7.	Fagara zanthoxyloides	Root Extract	Reversal of sickling.
8.	Terminalia catappa	Extract	Effective antisickling agent inhibiting osmotically induced haemolysis of human erythrocytes.
9.	Scoparia dulcis	Extract	Antisickling Activity
10.	Trypanosome brucei	Plant Extract	Antisickling Activity
11.	Alchornea cordifolia	Extract	Antidrepanocytary activity
12.	Afromomum albo violaceum	Extract	Antidrepanocytary activity
13.	Annona senegalensis	Extract	Antidrepanocytary activity
14.	Cymbopogon densiflorus	Extract	Antidrepanocytary activity
15.	Bridelia ferruginea	Extract	Antidrepanocytary activity
16.	Ceiba pentandra	Extract	Antidrepanocytary activity
17.	Morinda lucida	Extract	Antidrepanocytary activity
18.	Hymenocardia acida	Extract	Antidrepanocytary activity
19.	Coleus kilimandcharis	Extract	Antidrepanocytary activity
20.	Dacryodes edulis	Extract	Antidrepanocytary activity
21.	Caloncoba welwithsii	Extract	Antidrepanocytary activity
22.	Vigna unguiculata	Extract	Antidrepanocytary activity
23.	Zanthoxylum macrophylla	Crude aqueous root extract	Antisickling Activity (Membrane Stabilizer)
24.	Garcinia kola	Seeds	Antisickling Activity (Membrane Stabilizer)
25.	Senna alata	Crude aqueous root extract	Antisickling Activity (Membrane Stabilizer)
26.	Senna podocarpa	Crude aqueous root extract	Antisickling Activity (Membrane Stabilizer)
27.	Cajanus cajan	Seed Extract	Effective in restoring normal morphology of erythrocytes.
28.	Aged garlic	Extract	Suppresses hemolysis and prevents reduced membrane deformability.
29.	Carica papaya	Extract	Antisickling Activity
30.	Cssus populnea	Root Extract	Antisickling Activity
31.	Adansonia digitata	Extract	Antisickling Activity
32.	Cymbropogon citratus	Extract	Antioxidant Activity
33.	Camellia sinensis	Extract	Antioxidant Activity
34.	Scoparia dulcis	Extract	Antioxidant Activity
35.	Picrorhiza kurroa	Extract	Antioxidant Activity

Orthodox lines of treatment:

The induction of fetal hemoglobin has been the most promising of all the lines of orthodox treatment used in the management of sickle cell disease. Fetal hemoglobin is believed to interfere with the polymerized globin chains whose interaction with each other results in rigidity of the cells. In randomized adult patients’ trials, treatment of the patients with HU reduced the acute chest syndrome and the need for blood transfusions, also reducing the painful crises by as much as 50%. Successful use of HU was also reported in children. The use of blood transfusion has helped in sickle cell disease management but with some complications. Bone marrow transplantation in children has recorded good curative results in some patients. Nitric oxide, a potent vasodilator has been evaluated for its anti-sickling properties. Other orthodox lines of treatments being pursued include anti-adhesion and anti-oxidative therapies.¹⁵

Potentials of medicinal plants:

The use of phytomaterials such as Piper guineensis, Pterocarpa osun, Eugenia caryophyllala and Sorghum bicolor extracts for the treatment of sickle cell disease was reported.¹⁶The extract of Pterocarpus santolinoides and Aloe vera was reported to increase the gelling time of sickle cell blood and inhibits sickling in vitro. This indicates that such plants may indeed have a great potential in the management of sickle cell disorder. The reversal of sickling by root extracts of Fagara zanthoxyloides has also been reported.¹⁷Terminalia catappa could be an effective antisickling agent inhibiting osmotically induced haemolysis of human erythrocytes in a dose dependent basis.¹⁸ The use of Scoparia dulcis in the management of sickle cell disease by one woman for over two decades and the efficacy of the plant in the management of sickle cell disease was speculated. They therefore, used Trypanosome brucei to investigate the effect of the plant on hematological and biochemical indices due to lack of animal models for assessing the effectiveness of the plant extract in sickle cell disease monitoring.¹⁹ Crude aqueous extract of Zanthoxylum macrophylla roots as an anti-sickling agent was also highlighted and 2-hydroxybenzoic acid was isolated and identified as the anti-sickling agent obtained from the root of this plant. Garcinia kola is a popular seed consumed by the locals in Nigeria and it is also known as ‘bitter kola’. It has been speculated to be effective in the management of sickle cell disease. An investigation of the aqueous extracts of Garcinia kola to confirm the above claim indicated that it was higher and more effective on membrane stabilization than phenylalanine.²⁰ The membrane stabilization activity of aqueous extract of Zanthoxylum macrophylum roots was observed to be lower than phenylalanine which differs from the report on Garcinia kola. Senna alata and Senna podocarpa membrane stabilizing properties had been identified but the stabilizing activity was found to be higher in Senna alata. The pharmacological agents that alter membrane stability could be applied in the control of sickling process of erythrocytes, a major physiological manifestation of the sickle cell disease.²¹ Furthermore, it has been suggested, that the extract of the seed of the Cajanus cajan was effective in restoring normal morphology of erythrocytes from blood samples of patients affected by sickle cell anemia.²²Thus, Aged garlic could be useful in sickle cell management because it has been found to suppress hemolysis and prevented reduced membrane deformability.²³ Adansonia digitata L (Bambacacae) which was reported to be effective in treating sickle cell anemia patients was not active as an anti sickling agent in vitro. The resultant effect of the actions of these plants is the ability to manage sickle cell disease patients.²⁴

Bioactive constituents of medicinal plants used in sickle cell disease management:

Phytochemical examination of the extract of herbal formula Ajawaron whose main constituents are roots of Cssus populnea L. CPK was found to contain anthraquinones derivatives, steroidal glycosides and cardiac glycosides. Alkaloids and tannins were completely absent in CPK extracts. Furanoditerpene constituent isolated from Sphenocentrum jollyanun was used for the treatment of inflammation related diseases of which sickle cell is one of them.²⁵A compound isolated from Khaya senegalensis possessing antisickling activity was identified as rearranged limonoid.²⁶Scoparia dulcis has been reported to be rich in flavonoids and terpenes .5-hydrooxymethyl-2-furfural (5HMF), a naturally occurring aromatic aldehyde inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Other bioactive compounds isolated include epigallocatechin gallate from green tea, 2-dihdroxybenzoic acid from Zanthoxyllum macrophyla.²⁷The Nigerian Zanthoxylum has been extensively studied.²⁸ The bioactive compounds responsible for anti-sickling properties were identified as vanillic acid, p-hydroxy benzoic acid and p-fluoro benzoic acid. They were found to be active at low concentrations and the latter was the most active.²⁹

The role of anti-oxidants:

Oxidative damage to cells is believed to be responsible for activation of KCL-cotransport in sickled erythrocytes.³⁰The sickle cell erythrocytes are fragile and dehydrated and it is important that minerals and anti–oxidants are constantly supplied to maintain hydration and membrane integrity. Therefore many tropical plants have been investigated for their micronutrients and anti-oxidative properties. Some of the plants examined so far include M. charantia, Cymbropogon citratus and Camellia sinensis, Scoparia dulcis , Aged garlic and Picrorhiza kurroa.³¹

CONCLUSION:

Sickle cell disease is known to be one of the diseases ravaging most world populations cutting across nations and ethnic divide. But we see that the bioactive ingredients present in plants possess various therapeutic activity used in traditional practice and are mostly identified as traditional healers for the treatment of the disease. Since most plants have medicinal properties, it is of utmost importance that their efficacy is utilized for the treatment of sickle cell anaemia. It has also been concluded that males suffer more from the disease as the gene responsible for it is dominant and highly expressive while the females are generally carriers as the is recessive and does not express itself.

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Received on 13.01.2012 Modified on 29.01.2012