A REVIEW ON PHYTOCHEMICAL AND PHARMACOLOGICAL RESEARCH – REMEDY FOR SICKLE CELL DISEASE

A REVIEW ON PHYTOCHEMICAL AND PHARMACOLOGICAL RESERCH - REMEDY FOR SICKLE CELL DISEASE

Shilpa Vaishnava * and V. D. Rangari

SLT Institute of Pharmaceutical Sciences Guru Ghasidas Vishwavidyalaya, Bilaspur Chhattisgarh-495001, India.

ABSTRACT: Aim: This article focuses on the current review of world-wide medicinal plants studied for their phytochemical investigations, various biological activities and clinical studies in relation to their use for treatment of Sickle cell disease. Method: All relevant literature databases were searched up to 18 September 2014. The search terms were plant, herb, herbal therapy, phytotherapy, sickle cell anemia and antisickling agent. All of the human, animal, in vitro studies, and reviews were included. Antisickling agent, antioxidant, and ethnopharmacological effects were the key outcomes. Results: In vitro and in vivo studies in various herbs revealed that anthraquinones, anthocaynin, amino acids, caricapinoside, p-hydroxy benzoic acid etc. are the potent herbal constituents responsible for antisickling activity in sickle cell anemia patients and these herbal constituents can be further researched for development of a much safer and affordable medicine in future. Conclusion: This extensive literature review indicated the presence of large number of medicinal plants and their phytochemical constituents that can be of great interest for further research in search of the therapeutically active natural products for the treatment of sickle cell disease. However, it implies from the present review that comparatively very less number of medicinal plants have been explored in search of the constituents for the antisickling activity. Extensive medicinal plant research in the area of sickle cell disease may open completely new vistas and treatment strategies for this incurable genetic disorder

Osmosis, Osmotic Pumps,

Controlled Drug Delivery, Osmogen, Semi Permeable Membrane, Water Soluble Pore Formers

Sickle-cell disease (SCD) or sickle-cell anemia (SCA), a multisystem disease, is the most common monogenic disorder worldwide and is associated with acute illness and progressive organ damage ¹. Also known as drepanocytosis, it is an inherited blood disease confined to red blood cells (RBCs).

In SCD, the hemoglobin (Hb) protein molecules inside the RBCs are structurally defective and hence called abnormal Hb ². The basic defect in this disease is change in sixth position of beta globin chain in which glutamic acid, a polar amino acid, is replaced by valine, a non polar amino acid. This minute change inside the structure has peculiar property of transforming the usual oval shape of the RBCs into sickle shape in an oxygen-deficient environment. Due to this property, the molecule is called sickle cell Hb ³. Approximately 5% of the world’s population is healthy carriers of a gene for SCD. However, in some regions, the percentage of people who are carriers of SCD gene is as high as 25%. Each year, over 300,000 children are born affected by SCD and half of them die before the age of 5 years ^{4, 5}. This disease is more pronounced in poor countries located in the intertropical regions ⁶.

Etiology and Pathophysiology of Sickle-cell Disease:

Hb is a combination of heme and globin; heme consists of iron and porphyrin, and globin consists of 2 pairs of similar polypeptide chain (2 alpha/2 beta). In normal human, mainly 2 types of Hb is present ⁶ and the ratio of these Hb types changes during development of human body ⁷. That is, in fetus, the major Hb component is HbF (a2g2) while HbA (a2b2) is a minor component. In adults, HbA and HbA2 (a2d2) are major Hb content and HbF is present in minor quantities. The defected Hb found in SCD patients is known as HbS in which a glutamic acid is substituted by valneic acid. HbS is a tetramer (alpha2/beta S2), nonpolar molecule and polymerizes when deoxygenated ³. Because of this Hb damage, changes occur in physiology of RBCs. The changes that occur in normal hemoglobin from molecular level to functional level during its conversion to sickle hemoglobin has been demonstrated in Fig. 1.

FIG. 1:  CHANGES IN NORMAL HEMOGLOBIN TO SICKLE HEMOGLOBIN FROM MOLECULAR LEVEL TO FUNCTIONAL LEVEL

Because of deoxygenation various ion channels such as, gardos channel, K-Cl cotransport and Cl^- pathway, are activated, which present in RBCs ⁸. Polymerization of cells increases membrane permeability for Ca₂⁺⁺ and Na⁺ ions. Ca₂⁺⁺ activates Gardos channel (Ca₂⁺⁺ activated K⁺ channel), that channel increase the outlet of H₂O and K⁺. It will cause dehydration of sickle cell RBCs. Deoxygenation of sickle red cells also stimulates K-Cl cotransport in isotonic solutions at pH 7.4. Studies on K-Cl cotransport function have identified different triggers of activation, such as cell swelling, cell acidification, reduced cell magnesium (Mg) content, membrane oxidative damage, and high concentrations of urea ⁹. Studies on the conductive Cl- pathway indicate red cell dehydration. The movement of K⁺ must be accompanied by that of chloride (or other monovalent anions) to maintain electro neutrality ¹⁰. The overall changes that occour in the various ion channels have been illustrated in Fig. 2.

FIG. 2: EFFECT OF DEOXYGENATION ON VARIOUS ION CHANNEL PRESENT IN RBCs

Deoxygenation causes polymerization, leading to sickled erythrocytes. Vaso-occlusion results from the interaction of sickled erythrocytes with leukocytes and the vascular endothelium. Vaso-occlusion then leads to infarction, hemolysis, and inflammation. Inflammation enhances the expression of adhesion molecules in endothelium, increasing the tendency of sickled erythrocytes to adhere to the vascular endothelium. And it worsen vaso-occlusion condition ¹¹, reperfusion of the ischemic tissue generates free radicals and oxidative damage. The damaged erythrocytes release free hemoglobin in to the plasma, which strongly bind to nitric oxide, causing functional nitric oxide deficiency and contributing to the development of vasculopathy. There is a large amount of heterogeneity in the expression of SCD. The common complications in SCD are vaso-occlusion, acute chest syndrome, pulmonary hypertension, central nervous system disease, priapism, and avascular necrosis ¹².

Orthodox line of treatment:

Hydroxyurea represents the only major breakthrough in pharmacotherapy of SCD within the past 20 years and is the only drug that is approved by the U.S. Food and Drug Administration (FDA) for treatment of adults with SCD ¹³. Penicillin at some stages is given to control Streptococcus pneumoniae pathogen that causes bacteremia in children with SCD. There are no evidence-based guidelines for the treatment of SCD-associated acute pain episodes. Only a small number of analgesics like nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and ketorolac or other non-opioid analgesics like paracetamol can be prescribed. Other treatment is RBC transfusion to suppress HbS production and is the mainstay of secondary prevention of overt stroke in patients with SCD ¹⁴. The first-line clinical management of SCD includes medullar transplantation, repeated blood transfusion to stabilize the patient’s Hb level, and the use of chemical agents which interfere with the mechanism and/or kinetics of the sickling process. Unfortunately, all currently proposed therapies are quite expensive and have attendant risk factors in terms of clinical use ¹⁵. Therefore, there is a need for more definite and effective treatments for the SCD.

Managing sickle cell disease with herbs:

Herbal extracts have been used as medicine for decades in the management of various diseases ¹⁶. It is acknowledged worldwide that traditional medicine can be explored and exploited to be used alongside synthetic pharmaceutical products for enhanced health management. The use of natural products in attempts at inhibiting SCD could be as old as when the SCD was discovered. Folkloric history has indicated attempts made by inhabitants using plant derived recipes in various parts of the world to treat what they described as fever of crises, shifting joint pains, exacerbations especially during rainy seasons and constant abnormality of the blood, though relatively few have been validated scientifically. Very few ethnomedicinal remedies for the treatment of SCD have been reported in the literature due to secrecy attached to the treatments of this disease. Current review deals with list of medicinal plants as illustrated in table, which have been proven scientifically for the management of SCD and with possible reported mode of action Table 1.

TABLE 1: LIST OF MEDICINAL PLANTS, THEIR CONSTITUENTS AND PROBABLE MODE OF ACTION.

Some of the scientifically validated traditional herbal medicine for the management of SCD is discussed below with probable biological marker present and responsible to cure sickle cell disease.

The Root and bark of Fagara zanthoxyloides Lam. (Rutaceae) (syn. Zanthoxylum zanthoxyloides) is widely used in folk medicine for treatment and the prevention of disease crisis ¹⁷. Anti-sickling activity of F. zanthoxyloides was discovered when aqueous extract of this plant preserved the color of RBCs ¹⁸ and was later discovered to revert sickled Hb RBCs to normal Hb in in vitro study ¹⁹. The same aqueous extract also reported to activates the red cells membrane- bound enzymes Na+, K+-ATPase and Ca++-ATPase, which are involved in the sickling process ²⁰.

The major bioactive compounds responsible for anti-sickling properties present in the extract were identified burkinabins A, burkinabins B and burkinabins C¹⁷ and furthermore studies proved that presence of vanillic acid, p-hydroxy benzoic acid and p-fluoro benzoic acid could play a useful role in sickle cell disease ²¹. Fig.3.

FIG. 3: STRUCTURE OF BURKANABIN

Carica papya Linn (Caricaceae) is a perennial herbaceous plant. It is widely cultivated for consumption as a fresh fruit and juice. The fruits, leaves, seeds and latex are very well known and scientifically proven for its medicinal property ²². Unripe papaya fruit extract and leaf extract has reported to have antisickling activity and shown inhibited HbSS polymerization which indicates the potency of extract to hit on HbS polymerization target in attenuating SS cell sickling. It also indicates that efficacy is probably at the cell membrane level ²³.  Recent advancment shown led to the isolation and identification of a new antisickling agent 8(2-0-β-D-4, 5-anhydroglucitoyl 1→ 2glucopyranosyl carbonyl) dibenzo [b,e] [1,4] dioxine-2-carboxylic acid (named as caricapinoside) which is reported for the first time from Carica papaya and from natural sources ²⁴ Fig. 4.

FIG. 4: STRUCTURE OF CARICAPINOSIDE

Allium sativum, commonly known as garlic (Liliaceae) has been used throughout history for medicinal purposes. Investigations have supported that aged garlic extract have significant anti-oxidant activity of ²⁵ and oxidative phenomenon plays a significant role in the pathophysiology of SCD because oxidant damage in sickle RBC is most likely the consequence of the inherent instability of hemoglobin S ²⁶. Aged garlic extract (AGE) reported to have S-allylcysteine which has been reported as anti oxidant S-allylcysteine ²⁷ has been shown to significantly improve erythrocyte deformability through stabilization of erythrocyte membranes in sickle RBC ²⁸. Fig.5.

FIG. 5: STRUCTURE OF  S- ALLYL CYSTIENE

Hymenocardia acidai Tul (Euphorbiaceae) reported to have varying traditional medicinal use ²⁹ and recently also reported for their anti sickling activity by traditional healers ³⁰. The phytochemicals screening revealed the presence of carbohydrates, saponin, alkaloid, glycosides in leaves of H. acidai and alcoholic extracts of the leaves have been observed to reverse sickled human RBCs in a dose dependent manner in which RBCs have been change from sickle shape to normal biconcave cells and later observed to increase in size after 30 min ³¹, some studies also concluded the anti sickling activity of this plant because of  anthocynins present in this plants and structure elucidation of the compounds are still in progress ³².

Cajanus Cajan, (Fabaceae) important legume plant used as nutrient and rich source of vitamin and protein conatins free amino acids (phenylalanine most active), phenolic compounds (p hydroxybenzoic acid), tannins, globulins and saponins ³³. Crude alcoholic extracts of C. cajan were reported to inhibit sickling and also quickly revert normal morphology of already sickled erythrocytes ³⁴ while aqeous extract of the dried seeds of an C. Cajan which conatin p-hydroxybenzoic in high amount has shown reversal of pre sickeld erythrocytes (HbSS) ³⁵. A Phytomedicine named Ciklavit® has been also developed by two Nigeriean professors, claimed water extract of Cajanus cajan seed contain phenylalanine that is predominant antisickling agent ³⁶. Fig. 6.

FIG. 6:  STRUCTURE OF P HYDROXYBENZOIC ACID

Cyperus esculentus, (Cyperaceae) a monocotyledonous plant rich in energy content (starch, fat, sugars and protein), mineral (phosphorus, potassium),vitamins E and C and major constituents phytosterol was reported as preventing heart attacks, thrombosis and activates blood circulation, both alcohol and aqueous extracts of C. esculentus possess anti- sickling activity specifically anti-HbS gelation property in which HbS gelation reduced from 100% to 48.21% and 82.14% respectively (possibly as a result of some anti-sickling liposoluble factor) ³⁷ Fig.7.

FIG. 7: STRUCTURE OF CAMPESETEROL AND BETA SITOSTEROL

Xylopia aethiopic (Annonaceae), commonly known as Negro pepper or Ethiopian pepper has been reported to posses medicinal and nutritional values and its roots are well known for the treatment of rheumatism. Recent studies showed that aqeous extract fractions from X aethiopic were able to improve the Fe2³⁸+ /Fe3+ ratio, hence facilitating the conversion of methemoglobin to hemoglobin, increasing the oxygen affinity of sickle cell hemoglobin. Phytochemical studies revealed the presence of amino acids phenylalanine, tyrosine, Arginine, glutamic acid, and asparagine which were responsible for anti sickling property, this plant has showed best example of neutraceutical as anti sickling agent ³⁹.

Parquetina nigrescens, (Asclepiadaceae), also known as bullock is a shrub found in equatorial West Africa ⁴⁰ and has been in traditional medicine practice for centuries with its leaves, roots and latex all in use (Marks et al., 1995). It is also a major constituent of a commercial herbal preparation (Jubi formular) in Nigeria used in the treatment of anaemia in humans. Recent works on P. nigrescens leaf and stem extract showed inhibition of HbSS polymerization with the presence of amino acids ¹⁵.

Cissus populnea, (Vitaceae) associated with a myriad of medicinal uses in different parts of the world ⁴¹ the anti-sickling activities of  the roots extract is a major constituent of an herbal formula Ajawaron HF used in the management of sickle cell disease in Southwest Nigeria, phytochemical studies has confirmed the presence of anthraquinone derivatives i.e chrysaphanol, steroidal glycosides and cardiac glycosides in the plant which exhibited a relatively high antisickling activity compared with p-hydroxybenzoic acid and n-saline ⁴². Fig. 8.

FIG. 8: STRUCTURE OF CHRYSOPHANOL

Adansonia digitata L. belongs to the Bombacaeae family and is generally known as baobab.An investigation of the use of A. digitata bark during crises showed that the plant can reverse sickling ⁴³. Mpiana reported antisickling activity of A. digitata aqueous extract is dose dependent while Chemical screening on the aqueous extract of this plant revealed presence of anthocyanins and tannins. Based on previous work report on Congolese plants, A. digitata anthocynin extract tested for antisickling activity which has shown a good effect in the stabilization of sickle cell membranes and on Fe3+/Fe2+ ratio that play major role on managing sickle cell disease ⁴⁴.

CONCLUSION: The health care cost for management of SCD patients is disproportionately high compared to the number of people affected by the disease and common people cannot afford the high cost of treatment by Orthodox doctors. Considering all genetic disorders to which man is known to be liable, there is probably no other that presents a collection of problems and challenges quite comparable to SCD and related disorders. Due to the debilitating effect and cost of managing the SCD, research has been on-going to determine the efficacy of the use of medicinal plants to tackle the multiple challenges presented in sickle cell disease. Current review deals with all the aspects of herbal remedies which can be explored for much needed herbal management of sickle cell disease and gives all the information from Ethanobotnical use to the Phytochemistry of the plants explored for this disease. This review concludes that phytoconstituents such as anthraquinones, amino acids, caricapinoside, p-hydroxy benzoic acid etc. are the future herbal medicine for sickle cell anemia patients which will be a much safer and affordable medicine to the society.

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    Vaishnava S and Rangari VD: A Review on Phytochemical and Pharmacological Research - Remedy For Sickle Cell Disease. Int J Pharm Sci Res 2016; 7(2): 472-81.doi: 10.13040/IJPSR.0975-8232.7(2).472-81.

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