1.1.1. chloroquine, a prominent anti-malarial drug and

 1.1.1.      Purinealkaloids       Cola seeds contain purine bases chiefly represented by caffeine, rangingfrom 1.5 to 3.2% (2.5% on average in the dried drug) (Bruneton, 1998), it also containstraces of theobromine that ranges from 0.

02 to 0.08% and theophylline (Morton,1992).  The composition of C. nitida and C.

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acuminata seeds differ only quantitatively.  C.nitida contains a higher number of purine alkaloids (Seitz, 1992).                                                                                                     In a systematic analysis of different Cola accessions the caffeine andtheobromine content of C. acuminatawas determined as 4725-16138 mg/kg and 76-1277 mg/kg, respectively and 8624-19302 mg/kg and 37-1570 mg/kg for C.

nitida. The quantity of caffeine by the sum of the means was 21 fold higherthan theobromine (Niemenak, 2008).1.1.2.     Phenoliccompound       Thetannin content of Cola seeds is about  5-10%. Some other notable constituents are theflavan-3-ol type polyphenols: (+)-catechin,(-)-epicatechin, andproanthocyanidin dimers of group B (Bruneton, 1998).

Tannins also includecolatin, colatein, colanin (Heinrich, 2004).  The total phenolic content of 0.1 M HCl extract of Cola seed was determined as 49.36±2.

75 and 31.36±4.83, respectivelyin C. nitida and C. acuminata (expressed in mg equivalent of chlorogenic acid per gof fresh weight). Catechin was the major compound and represented 48.

93±2.5%and 51.18±2.2% of total soluble phenols (Boudjeko, 2009).                                                                                                      White and pink Cola acuminata seed (90% methanol extract) contains 3.37and 4.17 mg/100 g fresh weight total phenol, respectively. The same value forwhite, pink and red C.

nitida semenwas 4.45, 6- 12 and 9.09 (Odebode, 1996).

 2.      Biologicaland clinical activities of Cola seed 2.1.Antiplasmodial Activity       Malaria is known as seriousparasitic disease found majorly in the tropical regions that are caused byspecies of Plasmodium and transmitted by Anopheles mosquito’s species. It is commonin countries in Africa, Southeast Asia and South America. They are high death ratethat is reported in these regions. The exponential increment of resistance ofthe most severe and commonest form of Plasmodium species, Plasmodium falciparumto chloroquine, a prominent anti-malarial drug and first line drug over thepast two decades has necessitated the investigation into traditionally calmedanti-malarial plants. And amongst the commonly used anti-malarial plants inNigeria are Mangifera indica and Colanitida.

(F.O.Omoya) 2.2.  Cardiovascular Activity      The Investigationon the effect of aqueous extracts of different Cola seeds (C. acuminata, C. nitida subsp.

rubra, C. nitida subsp. Alba) on the steady activity of mammalian heart and metabolic ratewas carried out, this was done on male albino rats. Low concentrations of Cola seed extract triggered the heart. Thisincreased the rate and also force of contraction as well as the metabolic rate.With higher concentrations there was a reduced rate and amplitude of heartbeat.

Even at higher concentrations in heart failure case. The extract was added graduallyby increasing quantities of 0.2 ml each time. The calculated doses for animalsof different body weights were diluted to the following range of concentrations:2, 4, 8 and 10 mg/ml. Just as the concentration of the extracts was increased,this increased rate of metabolism up to a certain limit. The increase in basalmetabolic rate at high concentrations (8-10 mg/ml) was smaller than that atlower concentrations. The dose-response curves were similar for C.

acuminataand C. nitida subsp. rubra (C. nitida subsp. alba was not tested). C.

acuminataincreased the force of contraction by 40-60% and rate by 30- 47%. As thequantity of the Cola seed extractinjected was increased there was a corresponding decrease in both force ofcontraction and rate. C. nitidasubsp. rubra increased the force by13-20% and rate by 3%, while C. nitidasubsp.  alba increased the rate by 10-16% and force by 2%.

The force ofheart contraction was always the first to be affected, its decrease occurringbefore that of the heart rate. At even higher concentrations, the force ofcontraction was so severely reduced that heart failure resulted. Prior to heartfailure, the rate was reduced by 60-70% and the force by 80-90%.

The xanthinesstimulate the mammalian myocardium directly. In isolated mammalian heart, boththe rate of beat and force of contraction are increased by caffeine andtheophylline. (Chukwu, 2006).

 2.3. Effects onGastrointestinal system       The use of Cola beverages has been connected to the pathological process ofpeptic ulcer and also in the management of the ulcer disease. By administeringcaffeine to animals, this causes some pathological changes in thegastrointestinal tract and the formation ulcer. We do not know the exactmechanism in which Cola induces gastricacid secretion. However, there is increasing proof that cyclic AMP isimplicated in gastric acid secretion caused by the alkaloids. The induction ofgastric acid secretion by Cola couldbe entirely due to the presence in Cola ofthe xanthines or this may involve other gastric secretagogues in Cola that is not yet identified (Ibu,1986).

 2.3.1.      HormonalActivities        Thestudy of Solipuram characterized the androgenic and chemo-preventativeproperties of the C. acuminata usingandrogen receptor positive and negative cell lines.

Exposure of prostate cellsto the ether extract of C. acuminata  resulted in a growth inhibition (GI50) of 15ppm in LNCaP cells and 3.6 ppm in DU145 cells. The extract elicited a 2-foldincrease in the mRNA of the anti-apoptotic gene Bcl2, with a 10-fold increasein that of the proapoptotic gene Bax.

A 2.4- to 7.5-fold change in apoptoticcells was observed in both cell lines. The ether extract at 10 ppm elicited atime- and dose dependent stimulation of both the protein and mRNA levels ofseveral androgen-regulated genes. The extract caused a 36% decrease in PSAsecretion and a significant increase in PSA mRNA. The relative binding affinity(IC50) of the extract for androgen receptor (AR) was 2-5-fold lower than thatof the synthetic androgen R1881.

The ether extract was found to be a specificligand for the AR in that the natural ligand, DHT, and the anti-androgen,flutamide, displaced the extract bound to AR and inhibited Biz-2-inducedtranscription and PSA secretion (Solipuram, 2009).                                                                                                                      The oestrous cycles of rats treated withhydro-alcohol extracts (90 mg/kg intraperitoneal) of Cola nitida, were blocked at the dioestrous II stage. Only 50% ofthe cycles of rats treated with Colanitida were disrupted. The extract contains weak antioestrogen-likeactivity that provokes a blockage of female rat ovulation and oestrous cycle byacting on the hypophysis and/or hypothalamus secretion.

This effect wasmediated by oestrogen receptors (Benie, 2003).    2.3.2.

      Cytotoxity      Cytotoxic studies on human epidermoidcarcinoma (KB 3-1) cells revealed that, whereas a proanthocyanidin isolatedfrom C. acuminata caused a completeinhibition of the bloodstream trypanosomes (106 cells) at a concentration of 50µg/ml, the anti-trypanosomal compound showed no cytotoxicity toward mammaliancells at these concentrations. Cytotoxic effects of the compound were only observedat higher dosages (250 µg/ml), i.e. four-five times the amount ofproanthocyanidin needed to completely inhibit the growth of 106 trypanosomes.The pure proanthocyanidin as well as the ethanol extract had no effects onvarious strains of Escherichia coli, demonstrating that this newantitrypanosomical drug is highly specific to T. brucei (Kubata, 2004).

                                                                                                                                                  The purpose of the study of Fontenot wasto characterize the putative phytoestrogenic compounds present in C.acuminatafor Oestrogenic-like activity. As an initial step, five extracts (E1 – hexane,E2 – ether, E3 – acetone, E4 – methanol and E5 – water) were sequentiallygenerated using solid-liquid phase extraction and their bioactivity wasexamined in MCF-7, MDA-MB-468 and LNCaP cancer cell models. MTT cell viability,dye exclusion, caspase activity and microscopic assessment of apoptotic cellsdemonstrated that extracts of Colawere cytotoxic to MCF-7, MDA-MB 468 and LNCaP cells. In MCF-7 cells, theacetone extract (E3) at 100 ppm elicited a potent cytotoxic response with agrowth inhibitory concentration (GI50) of 67 ppm. In contrast, E3 stimulatedgrowth in LNCaP cells. The ether extract (E2) showed a dose-dependent cytotoxicresponse with a GI50 of 13 ppm in the LNCaP cell line.

Examination of theapoptotic response induced by E2 and E3 paralleled the level of cellcytotoxicity observed in both cell lines. The methanol extract (E4) was theonly extract that showed a time-, dose-, and oestrogen-receptor-dependentstimulation of pS2 gene expression. On the other hand, the acetone extract(E3), which showed the highest degree of cytotoxicity, showed no transcriptionstimulation of pS2 in MCF-7 cells (Fontenot, 2007).  2.4.Diuretic Effect       Caffeine is a mild stimulant and hasdiuretic properties and this is the main basis of the use of Cola seed.

Cola extracts are also astringent and anti-diarrheal due to thetannin content. Cola extracts areingredients of many tonics for depression and tiredness and to stimulate theappetite (Heinrich, 2004).                                                                                                                           Thepharmacodynamics properties of Colaseed may be interpreted on the basis of its caffeine content. Caffeine itselfis sometimes given in conjunction with other analgesics to produce stronger andquicker pain-killing actions, but there is no information of similarapplication of Cola seeds.Methylxanthines (caffeine, theobromine and theophylline) are used to treatpre-term infant apnea, chronic obstructive pulmonary disease, and especiallyasthma. They relax bronchial smooth muscle, stimulate cardiac muscle, and arediuretic (Blumenthal, 2000), however no such application is documented for Cola. The effects of the xanthinederivates on acid secretion have also been reported.

The pattern of theireffects depends upon the species and conditions employed. Humans are relativelysensitive, and moderate oral or parenteral doses of caffeine cause thesecretion of both acid and pepsin.       Theophyllinewas reported to be as potent as caffeine in this respect (Ibu, 1986).                                                                                                            Caffeine increases the free fatty acidand glucose level in plasma. The underlying mechanistic basis for these effectsis generally regarded to be a selective blockade of adenosine receptors viacompetitive inhibition, which are present in brain, blood vessels, kidneys,heart, gastrointestinal tract and respiratory passageways (Burdock, 2009). Froma therapeutic point of view, the most important effect of Cola is the central nervous system stimulatory activity, due to itscaffeine content.                                                                                                                                              The following actions were confirmed inanimal experiments for Cola seed:analeptic; stimulates production of gastric acid; lipolytic and increasesmotility. Compared to other methylxanthines, caffeine is a weaker diuretic andpositively chronotropic (Blumenthal, 2000).

 2.5.AntioxidantActivity        The effectiveness of certainantioxidant substances (among them Colaextracts) in the protection of red cells from oxidation and degradation withrespect to their window times of survival has been analyzed using UV-visiblespectrophotometry. In the presence of an oxidizing agent (potassiumferricyanide), lysis of red cell membrane, oxidation of exposed hemoglobin andmethemoglobin formation were observed for 12 hours. 70% methanol extracts C.

acuminata and C. nitida were effective as antioxidants in red cell survival andviability. The order of anti-oxidative potency was as follows: C.

acuminata (white)>C. nitida (pink)>C. nitida (red) (Atolaye 2009).  2.6.Anti-inflammatory Activity       Daels-Rakotoarison evaluated, in bothcell-free and cellular in vitro systems, the ability of decaffeinated Cola seed extracts to mitigate theinflammatory effects of polymorpho-nuclear neutrophilic-derived elastase viaprotection of ?-1-proteinase inhibitor.

The extracts were prepared fromfive-year-old Cola seeds and underrather stringent extraction conditions, followed by decaffeination withdichloromethane.   The resulting extractprimarily contained phenolic compounds. It was reported to inhibit bothelastase release and activity, presumably through its antioxidant properties(Daels-Rakotoarison, 2003). 2.7.Anti-diabetic Effect         Besides the fact that kolanut containcaffeine and act as a stimulant and anti-depressant, they are also thought toreduce hunger, aid digestion, and work as an aphrodisiac. In some parts ofAfrica, kolanut are given as gifts to visitors entering a home, usually withsome formal ceremony. Besides the ceremonial uses, many Africans consumekolanut regularly, even daily, for the medicinal effects such as diabetes.

Morerecently, kolanut extracts have become popular in Europe and North America as anatural or alternative medicine for the treatment of diabetes.       C. nitida seed exhibited antioxidantproperties and inhibited ?-amylase and ?-glycosidase (key enzyme linked totype-2 diabetes) activities as well as Fe 2+ induced lipid peroxidation in ratpancreas in vitro. This antioxidant and enzyme inhibition could be some of thepossible mechanism by which C. nitida isused in folklore for the management/ seeds through the inhibition of keyenzymes linked with type-2 diabetes (?-amylase and ?-glycosidase), therebymaking them a very good and cheap nutraceuticals for management/treatment oftype-2 diabetes. (Ganiyu Oboh, Kate E.

Nwokocha , Ayodele J. Akinyemi1,,Adedayo O. Ademiluyi.

2014)