1.1.1. The tannin content of Cola seeds is about


1.1.1.      Purine

       Cola seeds contain purine bases chiefly represented by caffeine, ranging
from 1.5 to 3.2% (2.5% on average in the dried drug) (Bruneton, 1998), it also contains
traces of theobromine that ranges from 0.02 to 0.08% and theophylline (Morton,
1992).  The composition of C. nitida and C. acuminata seeds differ only quantitatively.  C.
nitida contains a higher number of purine alkaloids (Seitz, 1992).                                                                                    

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      In a systematic analysis of different Cola accessions the caffeine and
theobromine content of C. acuminata
was 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 higher
than theobromine (Niemenak, 2008).


tannin content of Cola seeds is about  5-10%. Some other notable constituents are the
flavan-3-ol type polyphenols: (+)-catechin,(-)-epicatechin, and
proanthocyanidin dimers of group B (Bruneton, 1998). Tannins also include
colatin, 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, respectively
in C. nitida and C. acuminata (expressed in mg equivalent of chlorogenic acid per g
of 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 3.37
and 4.17 mg/100 g fresh weight total phenol, respectively. The same value for
white, pink and red C. nitida semen
was 4.45, 6- 12 and 9.09 (Odebode, 1996).


2.      Biological
and clinical activities of Cola seed


Antiplasmodial Activity

      Malaria is known as serious
parasitic disease found majorly in the tropical regions that are caused by
species of Plasmodium and transmitted by Anopheles mosquito’s species. It is common
in countries in Africa, Southeast Asia and South America. They are high death rate
that is reported in these regions. The exponential increment of resistance of
the most severe and commonest form of Plasmodium species, Plasmodium falciparum
to chloroquine, a prominent anti-malarial drug and first line drug over the
past two decades has necessitated the investigation into traditionally calmed
anti-malarial plants. And amongst the commonly used anti-malarial plants in
Nigeria are Mangifera indica and Cola
nitida. (F.O.Omoya)


2.2.  Cardiovascular Activity

      The Investigation
on 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 rate
was carried out, this was done on male albino rats. Low concentrations of Cola seed extract triggered the heart. This
increased 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 gradually
by increasing quantities of 0.2 ml each time. The calculated doses for animals
of 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 basal
metabolic rate at high concentrations (8-10 mg/ml) was smaller than that at
lower concentrations. The dose-response curves were similar for C. acuminata
and C. nitida subsp. rubra (C. nitida subsp. alba was not tested). C. acuminata
increased the force of contraction by 40-60% and rate by 30- 47%. As the
quantity of the Cola seed extract
injected was increased there was a corresponding decrease in both force of
contraction and rate. C. nitida
subsp. rubra increased the force by
13-20% and rate by 3%, while C. nitida
subsp.  alba increased the rate by 10-16% and force by 2%. The force of
heart contraction was always the first to be affected, its decrease occurring
before that of the heart rate. At even higher concentrations, the force of
contraction was so severely reduced that heart failure resulted. Prior to heart
failure, the rate was reduced by 60-70% and the force by 80-90%. The xanthines
stimulate the mammalian myocardium directly. In isolated mammalian heart, both
the rate of beat and force of contraction are increased by caffeine and
theophylline. (Chukwu, 2006).


2.3. Effects on
Gastrointestinal system


      The use of Cola beverages has been connected to the pathological process of
peptic ulcer and also in the management of the ulcer disease. By administering
caffeine to animals, this causes some pathological changes in the
gastrointestinal tract and the formation ulcer. We do not know the exact
mechanism in which Cola induces gastric
acid secretion. However, there is increasing proof that cyclic AMP is
implicated in gastric acid secretion caused by the alkaloids. The induction of
gastric acid secretion by Cola could
be entirely due to the presence in Cola of
the xanthines or this may involve other gastric secretagogues in Cola that is not yet identified (Ibu,


2.3.1.      Hormonal


study of Solipuram characterized the androgenic and chemo-preventative
properties of the C. acuminata using
androgen receptor positive and negative cell lines. Exposure of prostate cells
to the ether extract of C. acuminata  resulted in a growth inhibition (GI50) of 15
ppm in LNCaP cells and 3.6 ppm in DU145 cells. The extract elicited a 2-fold
increase in the mRNA of the anti-apoptotic gene Bcl2, with a 10-fold increase
in that of the proapoptotic gene Bax. A 2.4- to 7.5-fold change in apoptotic
cells was observed in both cell lines. The ether extract at 10 ppm elicited a
time- and dose dependent stimulation of both the protein and mRNA levels of
several androgen-regulated genes. The extract caused a 36% decrease in PSA
secretion 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 that
of the synthetic androgen R1881. The ether extract was found to be a specific
ligand for the AR in that the natural ligand, DHT, and the anti-androgen,
flutamide, displaced the extract bound to AR and inhibited Biz-2-induced
transcription and PSA secretion (Solipuram, 2009).                                                                                                               

      The oestrous cycles of rats treated with
hydro-alcohol extracts (90 mg/kg intraperitoneal) of Cola nitida, were blocked at the dioestrous II stage. Only 50% of
the cycles of rats treated with Cola
nitida were disrupted. The extract contains weak antioestrogen-like
activity that provokes a blockage of female rat ovulation and oestrous cycle by
acting on the hypophysis and/or hypothalamus secretion. This effect was
mediated by oestrogen receptors (Benie, 2003).





2.3.2.      Cytotoxity

      Cytotoxic studies on human epidermoid
carcinoma (KB 3-1) cells revealed that, whereas a proanthocyanidin isolated
from C. acuminata caused a complete
inhibition of the bloodstream trypanosomes (106 cells) at a concentration of 50
µg/ml, the anti-trypanosomal compound showed no cytotoxicity toward mammalian
cells at these concentrations. Cytotoxic effects of the compound were only observed
at higher dosages (250 µg/ml), i.e. four-five times the amount of
proanthocyanidin needed to completely inhibit the growth of 106 trypanosomes.
The pure proanthocyanidin as well as the ethanol extract had no effects on
various strains of Escherichia coli, demonstrating that this new
antitrypanosomical drug is highly specific to T. brucei (Kubata, 2004).                                                                                                                                            

     The purpose of the study of Fontenot was
to characterize the putative phytoestrogenic compounds present in C.acuminata
for Oestrogenic-like activity. As an initial step, five extracts (E1 – hexane,
E2 – ether, E3 – acetone, E4 – methanol and E5 – water) were sequentially
generated using solid-liquid phase extraction and their bioactivity was
examined in MCF-7, MDA-MB-468 and LNCaP cancer cell models. MTT cell viability,
dye exclusion, caspase activity and microscopic assessment of apoptotic cells
demonstrated that extracts of Cola
were cytotoxic to MCF-7, MDA-MB 468 and LNCaP cells. In MCF-7 cells, the
acetone extract (E3) at 100 ppm elicited a potent cytotoxic response with a
growth inhibitory concentration (GI50) of 67 ppm. In contrast, E3 stimulated
growth in LNCaP cells. The ether extract (E2) showed a dose-dependent cytotoxic
response with a GI50 of 13 ppm in the LNCaP cell line. Examination of the
apoptotic response induced by E2 and E3 paralleled the level of cell
cytotoxicity observed in both cell lines. The methanol extract (E4) was the
only extract that showed a time-, dose-, and oestrogen-receptor-dependent
stimulation of pS2 gene expression. On the other hand, the acetone extract
(E3), which showed the highest degree of cytotoxicity, showed no transcription
stimulation of pS2 in MCF-7 cells (Fontenot, 2007).



Diuretic Effect

      Caffeine is a mild stimulant and has
diuretic properties and this is the main basis of the use of Cola seed. Cola extracts are also astringent and anti-diarrheal due to the
tannin content. Cola extracts are
ingredients of many tonics for depression and tiredness and to stimulate the
appetite (Heinrich, 2004).                                                          
pharmacodynamics properties of Cola
seed may be interpreted on the basis of its caffeine content. Caffeine itself
is sometimes given in conjunction with other analgesics to produce stronger and
quicker pain-killing actions, but there is no information of similar
application of Cola seeds.
Methylxanthines (caffeine, theobromine and theophylline) are used to treat
pre-term infant apnea, chronic obstructive pulmonary disease, and especially
asthma. They relax bronchial smooth muscle, stimulate cardiac muscle, and are
diuretic (Blumenthal, 2000), however no such application is documented for Cola. The effects of the xanthine
derivates on acid secretion have also been reported. The pattern of their
effects depends upon the species and conditions employed. Humans are relatively
sensitive, and moderate oral or parenteral doses of caffeine cause the
secretion of both acid and pepsin.       Theophylline
was reported to be as potent as caffeine in this respect (Ibu, 1986).                                                                                                      

      Caffeine increases the free fatty acid
and glucose level in plasma. The underlying mechanistic basis for these effects
is generally regarded to be a selective blockade of adenosine receptors via
competitive inhibition, which are present in brain, blood vessels, kidneys,
heart, gastrointestinal tract and respiratory passageways (Burdock, 2009). From
a therapeutic point of view, the most important effect of Cola is the central nervous system stimulatory activity, due to its
caffeine content.                          

   The following actions were confirmed in
animal experiments for Cola seed:
analeptic; stimulates production of gastric acid; lipolytic and increases
motility. Compared to other methylxanthines, caffeine is a weaker diuretic and
positively chronotropic (Blumenthal, 2000).



        The effectiveness of certain
antioxidant substances (among them Cola
extracts) in the protection of red cells from oxidation and degradation with
respect to their window times of survival has been analyzed using UV-visible
spectrophotometry. In the presence of an oxidizing agent (potassium
ferricyanide), lysis of red cell membrane, oxidation of exposed hemoglobin and
methemoglobin formation were observed for 12 hours. 70% methanol extracts C. acuminata and C. nitida were effective as antioxidants in red cell survival and
viability. The order of anti-oxidative potency was as follows: C. acuminata (white)>C. nitida (pink)>C. nitida (red) (Atolaye 2009).


Anti-inflammatory Activity

       Daels-Rakotoarison evaluated, in both
cell-free and cellular in vitro systems, the ability of decaffeinated Cola seed extracts to mitigate the
inflammatory effects of polymorpho-nuclear neutrophilic-derived elastase via
protection of ?-1-proteinase inhibitor. The extracts were prepared from
five-year-old Cola seeds and under
rather stringent extraction conditions, followed by decaffeination with
dichloromethane.   The resulting extract
primarily contained phenolic compounds. It was reported to inhibit both
elastase release and activity, presumably through its antioxidant properties
(Daels-Rakotoarison, 2003).


Anti-diabetic Effect

        Besides the fact that kolanut contain
caffeine and act as a stimulant and anti-depressant, they are also thought to
reduce hunger, aid digestion, and work as an aphrodisiac. In some parts of
Africa, kolanut are given as gifts to visitors entering a home, usually with
some formal ceremony. Besides the ceremonial uses, many Africans consume
kolanut regularly, even daily, for the medicinal effects such as diabetes. More
recently, kolanut extracts have become popular in Europe and North America as a
natural or alternative medicine for the treatment of diabetes.

       C. nitida seed exhibited antioxidant
properties and inhibited ?-amylase and ?-glycosidase (key enzyme linked to
type-2 diabetes) activities as well as Fe 2+ induced lipid peroxidation in rat
pancreas in vitro. This antioxidant and enzyme inhibition could be some of the
possible mechanism by which C. nitida is
used in folklore for the management/ seeds through the inhibition of key
enzymes linked with type-2 diabetes (?-amylase and ?-glycosidase), thereby
making them a very good and cheap nutraceuticals for management/treatment of
type-2 diabetes. (Ganiyu Oboh, Kate E. Nwokocha , Ayodele J. Akinyemi1,,
Adedayo O. Ademiluyi. 2014)