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COMPARATIVE STUDY OF THE EFFECTS OF AQUEOUS EXTRACTS OF MORINGA OLEIFERA AND VERNONIA AMYGDALINA LEAVES ON SOME BIOCHEMICAL INDICES IN ALBINO RATS

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ABSTRACT

A comparative  study of the  effects  of aqueous  extract  of Moringa  oleifera  and  Vernonia amygdalina on selected biochemical indices of prostate pathologies of male  albino rats was investigated  using thirty two  adult male albino  rats of average  weight  of 152g.  Rats were randomly assigned into four groups of eight rats each with different recognizable codes. Group one served as the control and each rat in this group received orally 2ml of distill water daily. Groups two and three received oral administrations of 2ml aqueous extract containing 5g of M. oleifera,  V. amygdalina  respectively daily. Group  four received  4ml containing 2.5g of M. oleifera with 2.5g of V. amygdalina per body weight orally daily. Administration of the extract was done for 28 days. The rats were fed on growers match and tap water ad libitum throughout the experiment. The animals were housed in standard animal cages in the animal house of the Department of Biochemistry, Kogi State University, Anyigba under 12 hour light/ dark cycle for 29 days. Changes in weight were noted at the end of every week for the four weeks. The animals were starved over-night and blood drawn from cut at the tip of the tails was used for fasting blood glucose test. All the animals were killed on the 29th day by jugular puncture; part of their blood was collected into plain bottle and spun to obtain serum, and part into  EDTA bottle for biochemical analyses. A non significant weight increase was observed till the third week of administration of the extract followed by a decrease in weight in the fourth week. The group administered a combination of the extracts of M. oleifera with V. amygdalina showed a significant decrease (P<0.05) when compared to the control. A significant reduction (p<0.01) in the fasting blood glucose (FBS) was recorded in the group administered M. oleifera alone and the combination of M. oleifera with V. amygdalina when compared to the control value. An increase in the Packed Cell Volume was recorded in all the groups but were not significant (P>0.05). A significant increase in the total protein was recorded for the group administered V. amygdalina  and the  combination of M. oleifera with V. amygdalina.  A significant  increase (p<0.05)  and  (p<0.01)  in  the  serum  globulin  concentration  was  observed  in  the  group administered only V. amygdalina and the group administered the combination respectively. M. oleifera increased  serum albumin compared  to the V. amygdalina  and the  combination,  but decreased the serum bilirubin concentration relative to V. amygdalina and the combination. A significant  increase  (p<0.001)  and  (p<0.05)  in  the  urea  level  was  observed  in  the  group administered  the combination of M. oleifera and V.  amygdalina  and the group administered only M. oleifera respectively when compared to the control value. For serum electrolyte, there was an equivalent increase in serum potassium ion in all the groups but not significant (P>0.05) when compared to the control value. Both plant leaf extracts reduced the serum chloride ion but the combination did it better. M. oleifera recorded a significant reduction in serum sodium ion compared  to  V.  amygdalina  and  the combination  but  their  differences  was  not  significant (P>0.05). For serum lipid profile, V. amygdalina has a significant reduction (p<0.05) potential over  M.  oleifera  for total cholesterol.  V. amygdalina  and  the combination  increased  HDL compared to M. oleifera but not significant (P>0.05). LDL decreased significantly (P<0.05) in the combined extract relative to the single. Significant decreases (p<0.001) in Prostatic Acid Phosphatase (PAP) and Total Acid Phosphatase (TAP) activities were recorded in the entire intervention group when compared to the control value. However,  the two plants showed a reduction potential in metabolic factors associated with prostate disorders and their markers, PAP and TAP.

CHAPTER ONE

INTRODUCTION

1.1       Prostate

The prostate is a gland found only in males. It is located in front of the rectum and below the urinary bladder and vas deferens. The prostate secretes an alkaline fluid that forms part of the semen. The size of the prostate varies with age. In younger men, it is about the size of a walnut, but it can be much larger in older men.

The prostate makes some of the fluid that protects and nourishes sperm cells in semen, making the semen more liquid. Just behind the prostate are glands called seminal vesicles that make most of the fluid for semen. The urethra, the tube that carries urine and semen out of the body through the penis, goes through the center of the prostate.

The prostate starts to develop before birth. It grows rapidly during puberty, fueled by male hormones (called  androgens)  in the body. The main androgen,  testosterone,  is  made in the testicles. The enzyme 5-alpha reductase converts testosterone into dihydrotestosterone (DHT). DHT  is the  main  hormone  that  signals  the prostate  to  grow  (Lu-Yao,  2008).The  prostate usually stays at about the same size or grows slowly in adults, as long as male hormones are present.

1.1.1    Prostate pathologies

The prostate is usually affected with three major disorders namely; benign prostate hyperplasia, prostatitis and prostate cancer. These are disorders associated with males  over  the age of 40 years and impact on their health in general (McNaughton et al., 2001).

1.1.1.1 Benign Prostate Hyperplasia (BPH)

Benign prostate hyperplasia (BPH) is an age-related non cancerous enlargement of the prostate that results from a neoplastic unregulated growth of the prostate gland (Paglone, 2010). It is a disorder associated with males over the age of 40 years and impacts on their health in general (McNaughton et al., 2001).

Most common symptoms of BPH include; increased  frequency of urination during the  day, nocturia, straining to force urine out, urgency to urinate, decrease in strength of the  urinary stream’s diameter. Severe cases of BPH may lead to sepsis, irreversible bladder damage, renal failure or even death (Roehrborn and McConnell, 2002). Perhaps one fourth of men have some

degree of hyperplasia by the fifth decade of life. By the eight decade, over 90% of males would have prostatic hyperplasia. However, in only a minority of cases (about 10%) will hyperplasia be symptomatic and severe enough to require surgical or medical therapy (Bushman, 2009). BPH occurs significantly  only in men and dogs during aging,  though  there are significant differences  in BPH between the two species.  In humans, BPH  originates as nodules in the glands and stroma of the transition  zone.  Massive  enlargement  and glandular  proliferation occur within the noodles in men older than 70 years (Jeyaraj et al., 2000).

In dogs, BPH consists largely of glandular  acini, with minimal contribution from the  fibro muscular  stroma  (Walsh  and  Wilson,  1976).  Lower  urinary  tract  symptoms  (LUTS)  and bladder  outlet  obstruction  (BOO)  are  the  clinical  presentations  of  BPH  in  men,  while constipation is the symptom associated with BPH in dogs (Isaacs, 1984; Jeyaraj et al., 2000). Clinical manifestation of BPH occur only after prostatic growth has  taken place to such an extent  (usually  within  the  transition  zone  of  the  prostate)  that  impairs  bladder  emptying, resulting  in  lower  urinary  tract  symptoms  (LUTS)  and  bladder  outlet  obstruction  (BOO) (McNeal, 1984; Walsh, 1984). The natural history of BPH therefore involves the pathological and the clinical phases.

The pathological  phase is asymptomatic  and involves  the progression  from microscopic  to macroscopic BPH. It involves the development of hyperplastic change in the transition zone of the prostate (McNeal, 1978). Microscopic BPH develops in all men who live long enough but only half of them progress to macroscopic BPH (Ziada et al., 1999; Wei et al., 2005).

The clinical phase of BPH involves  the progression  from pathological  to clinical  BPH.  In

clinical BPH, the ratio of stroma to epithelium is 5:1, whereas in pathological BPH, the ratio is

2.7:1. The stroma therefore contributes significantly to the intravescical  obstruction seen  in clinical BPH (Akduman and Crawford, 2001).

The clinical symptoms of BPH are classified as obstructive (hesitancy, straining, decreased rate of  urine  flow),  urinary  retention  and  post-void  dribbling  and  irritative  symptoms  (urinary urgency, urinary frequency and nocturia). But the later have a greater impact on quality of life, while symptom severity correlates well with overall health status (Barry, 2001; Scarpa, 2001; Eaton, 2003). Symptomatic BPH consists of two components; a  static component related to prostatic tissue mass, and a dynamic component related to prostatic smooth muscle tone (Ejike and Ezeanyika, 2007).

1.1.2 Etiology of BPH

The etiology of BPH is still poorly understood.  However,  it seems that the  patho-etiology mechanism is endocrine controlled and involves alterations in the metabolism of androgen and estrogens (Suzuki et al., 1995), and androgen/estrogen imbalance (Obidoa, 2007), also, growth and cyto-differentiation  of the prostate (including  aberrant growth), under hormonal control (Ball and Risbridger, 2003). Increased intakes of energy, proteins and certain polyunsaturated fats in the diet may be associated with  modest increases in the risk of BPH, including pre- neoplastic   lesion  in  the  prostate   gland   due  to  increased   proliferation   and  associated inflammation (Heber, 2002).

The  adult  prostate  gland  is derived  from  the  urogenital  sinus  and  is  a relatively  growth- quiescent organ (in the absence of disease) in which there is a balance between the levels of cell proliferation and death (Bianco et al., 2002). The growth of the prostate rise from 1 gram at birth to about 4 grams before puberty, and then to an average of 20 grams after virilization (say by age 20 years) (Berry et al., 1984; Isaacs, 1984; Meikle et al., 1997). This period is regarded as the  adolescent  growth spurt, and it coincides  with  an increase  in testosterone  secretion (though BPH never occur then). There is however a later period of growth, starting probably in the fifth decade when androgen levels begin to drop and BPH paradoxically develops (Horton,

1992).There  is also  evidence  that  metabolic  disturbances  may promote  BPH  pathogenesis. Metabolic disturbances typified by the metabolic syndrome are known to increase insulin and insulin-like  growth  factor  levels  and  high  serum  concentrations  of  insulin  and  IGF-1  are associated with clinical benign prostate hyperplasia (Chokkalingam et al., 2002; Dahle et al.,

2002; Parsons et al., 2006; Ejike and Ezeanyika, 2008).

1.1.3 Prostatitis

Prostatitis refers, in its strictest sense, to the histological (microscopic) inflammation of  the tissue of the prostate gland. Prostatitis can be associated with an appropriate response of the body to an infection, but it also occurs in the absence of infection (Curtis, 1999; Krieger et al.,

1999).

Prostatitis is classified into the following;

Acute prostatitis: this is a bacterial infection of the prostate gland that requires urgent medical treatments.  It is characterized  with pains and presence  of white blood cells  (WBCs)  in the urine.

Chronic  bacterial  prostatitis:  This  is  a  relatively  rare  condition  that  usually  presents  as intermittent urinary tract infections. It is usually accompanied with or without pain with white blood cells in the blood.

Chronic  prostatitis/  chronic  pelvic  pain  syndrome:  This  is  the  most  common  but  least understood form of prostatitis which may be found in men of any age. It may be inflammatory or non-inflammatory and always accompanied by pains and non-bacterial (Habermacher et al.,

2006).

Asymptomatic inflammatory prostatitis: this does not have any history of genitourinary pain but there is a presence of leucocytes, usually during evaluation for other conditions. Between 6-

19% of men have pus cells in the semen but no symptoms (Korrovits et al., 2008).

1.1.4 Prostate cancer

Prostate cancer is the most common malignancy and the second most common cause of cancer deaths in males. It has long been taught that men die with prostate cancer rather than from it. However,  25% of men who  have prostate  cancer  die from the disease,  whilst  many more experience substantial morbidity (Zelefsky et al., 2008). The incidence has risen over the past decade,  although  this  increase  may  be  partly  due  to  more  frequent  diagnosis,  following heightened  community awareness and the introduction of  tests such as the measurement  of serum prostate specific antigen (PSA) (Michael, 2013). Several types of cells are found in the prostate, but almost all prostate cancers develop  from the gland cells. Gland cells make the prostate fluid that is added to the semen. The medical term for a cancer that starts in gland cells is  adenocarcinoma.  Other  types  of  cancer  can  also  start  in  the  prostate  gland,  including sarcomas, small cell carcinomas, and transitional cell carcinomas. But these types of prostate cancer are so rare that if you have prostate cancer, it is almost certain to be an adenocarcinoma. Some prostate cancers can grow and spread quickly, but most grow slowly. In fact, autopsy studies show that many older men (and even some younger men) who died of other diseases also had prostate cancer that never affected them during their lives. In many cases neither they nor their doctors even knew they had it (Dearnaley, 1994).

1.1.5 Androgens

Androgens, also called ‘androgenic hormone’ or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the  development

and maintenance of male characteristics in vertebrates by binding to androgen receptors. The primary well known androgen is testosterone, produced largely (95%) by the leydig cells of the testis, it is the major circulating androgen,  but must first be reduced to  dihydrotestosterone

(DHT) by the enzyme, 5α-reductase (NADP+ -ene-oxidoreductase; E.C: 1.3.1.22) for maximal

androgenic activity in the prostate (Pasupuleti and Horton, 1990; Wright et al., 1999; Bartsch et al., 2002).

1.2       Functions of androgens

During puberty, androgen, luteinizing hormone (LH) and follicle stimulating hormone (FSH) production increase, and the sex cord hollow out, forming the seminiferous tubules, and the germ  cells  start  to  differentiate  into  sperm.  Throughout  adulthood,  androgens  and  FSH cooperatively act on sertoli cells in the testis to support sperm production (Stephen and Saffron, 2001).

Inhibition of fat deposition by blocking a signal transduction pathway that normally supports adiposity function. This probably is the reason why males typically have less body fat than females. Androgens also increase beta-adrenergic receptors while decreasing alpha adrenergic receptors-which result in increased levels of epinephrine/ nor-epinephrine due to lack of alpha- 2-receptor   negative   feedback   and   decreased   fat   accumulation   due   to   epinephrine/nor epinephrine acting on lipolysis-inducing beta receptors (Singh et al., 2006).

Androgens promote the enlargement of skeletal muscle cells and probably act in a coordinated manner to function by acting on several cell types in skeletal muscle tissue which makes males to have more skeletal muscle mass than females, increased expression of androgen receptor due to higher androgen levels (Vlahopoulos et al., 2005).

Circulating  levels  of  androgens  can  influence  human  behavior  because  some  neurons  are sensitive  to  steroid  hormones.  Androgen  levels  have  been  implicated  in the  regulation  of human aggression and libido (Singh et al., 2006).  Indeed, androgens are capable of altering the structure of the brain in several species,  including  mice, rats, and  primates,  producing  sex differences (Zuloaga et al., 2008).

1.2.1 Androgens and prostate disorders

Physiologic functions and pathologic conditions of the prostate, like all other endocrine glands, are  regulated  by numerous  endogenous  hormones  and  growth  factors.  Testosterone  is the predominant  circulating  androgen  in  males.  It  is  a  steroid   hormone,  synthesized  from cholesterol in leydig cells within the interstitial of the testis.  Its production is stimulated  by luteinizing hormone (LH), secreted  by the anterior  pituitary gland in response to the cyclic

release  of  luteinizing  hormone  releasing  hormone  (LHRH)  by  the  hypothalamus.  LHRH release,  in a negative  feedback  fashion,  is inhibited  by testosterone.  Greater  than  95% of endogenous androgen is produced by testis, with the remainder produced as androstendione by adrenal cortex. This small amount of non testicular androgens has a minimal impact on prostate function in physiologically  normal males  (Partin  and  Rodriguez,  2002). Testosterone,  once taken up form the systemic circulation by the prostatic glandular and stromal cells and within the prostate, testosterone is rapidly and irreversibly converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (5AR). This leads to a five fold higher concentration of DHT versus testosterone  within the  intracellular  prostate,  versus an eleven-fold  higher  concentration  of testosterone within the circulation. DHT binds to the androgenic receptor within the cytosol, is actively transported  into the nucleus, and serves as a transcription  factor for prostatic gene expression  and  thus  cellular  function.  The  higher  concentration  of  intracellular  DHT,  in addition to its higher affinity for the androgen, supports the importance of 5AR in normal and pathological prostate physiology (Partin and Rodriguez, 2002).

As men age, serum levels of testosterone drop while those of estradiol and prolactin increase. The  prostate  is  particularly  sensitive  to  this  alteration  in  the  balance  of  these  hormones. Prolactin is a pro-lactation hormone that is also induced under stress conditions as the case in career  and  family stress  that  come  with  the middle-ages.  The  binding  of prolactin  to  the prostatic  cells  increase  the  activity  of  5AR  and  the  androgen  receptor  thereby  increasing androgen binding and uptake (McPherson et al.,  2001). With age, the level of sex hormone binding globulin, otherwise called testosterone binding globulin (to reflect its higher affinity for testosterone), increases. Sex hormone binding globulin (SHBG) bind about 44% of testosterone while albumin binds about 54%, leaving only 2% circulating unbound or free. Only this free testosterone  and  the  fraction  bound  to  albumin  are  available  to  interact  with  testosterone sensitive tissues. This is because the circulating dimeric form of SHBG has a molecular mass of approximately 90kDa (thus preventing it from traversing the capillary barrier) (Hammond,

2002).  Increase  in  SHBG  therefore  reduces  available  testosterone,  thereby  causing  the relaxation  of the  negative  feedback  inhibition  that  regulates  testosterone  action,  and  more testosterone is produced (Ejike and Ezeanyika, 2009).

1.2.3    Estrogens

Estrogens in its natural form are steroid hormones, while some synthetic ones are non-steroidal. Estrogens   are  compounds   named   for  their  importance   in  both   menstrual   and  estrous reproductive cycles. They are primary female sex hormones.

Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the  expression of many genes (Whitehead  and Nussey,  2001), as well activate  G- protein-  coupled  receptor, GPR30 (Prossnitz et al., 2007), the estrogen: estrogen receptor (ER) complex binds to specific DNA sequence called a hormone response element to activate the transcription of target genes (Lin, 2004). Estrogens are present in both men and  women but significantly higher level in women of reproductive age where they promote the development of female secondary sexual characteristics, such as breast, and are also involved in the thickening of the endometrium, and regulation of menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important for the maturation of sperm (Hess et al., 1997; and necessary for a healthy libido (Hill et al., 2004).

1.2.3 Functions of estrogens

Estrogens perform some structural functions which include;

Promotion of formation of female secondary sex characteristics,  acceleration of metabolism, increase  of  fat  stores,  endometrial  growth  stimulation,  increase  uterine  growth,  vaginal lubrication increase as well as thickening of its wall, reduce bone resorption, and increase bone formation, maintenance of vessel and skin.

Protein synthesis by increased hepatic production of binding proteins.

In blood coagulation by increasing circulating levels of factors 2, 7,9,10, plasminogen, decrease in anti-thrombin III, and increasing platelet adhesiveness.

In  lipid  metabolism   by  increasing  high  density  lipoprotein  (HDL),  triacylglycerol   and decreased LDL, fat deposition.

In fluid balance (salt and water retention)

In gastrointestinal tract by reducing bowel motility and increasing cholesterol in bile.

In melanin by increasing pheomelanin, reduce eumelanin and in lung function by supporting alveoli (Massaro and Massaro, 2004).

Estrogen together with progesterone promotes and maintains the uterus lining in preparation for

implantation of fertilized egg and maintenance of uterus function during gestation period,  as well as up-regulating oxytocin receptor in myometrium.

During ovulation, surge in estrogen levels induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the grafian follicle in the ovary.

Estrogen  also  promotes  sexual  receptivity  (Christensen  et  al.,  2011),  and  induce  lordosis behavior (Handa et al., 2012). It also promotes sexual desire (Warnock et al., 2005).

1.2.5    Metabolic factors associated with prostate pathologies

The metabolic syndrome describes a clinical constellation of metabolic abnormalities such as insulin resistance,  increased  level of central (visceral)  adiposity/obesity,  low levels  of high density lipoprotein and elevated  triacylglycerols,  impaired  fasting glucose  and  hypertension (Grundy  et  al.,  2004).  It  has  been  suggested  that  some  prostate  pathologies,  like  BPH represents a prostate growth path, promoted by oxidative stress,  inflammatory mediators and insulin-like growth factor (IGF) systems (Khandawala et al., 2000; Wang et al., 2004). There are evidences  that metabolic  syndrome  is linked  to,  and may lead  to prostate  pathologies (Kasturi et al., 2006; Ozden et al., 2007).  Hyperinsulinemia  and insulin resistance,  both of which accompany obesity,  and  are  known  features  of adiposity,  result  in the  deregulation and/or over-expression  of the  IGF system.  These have been shown to be involved  in both benign   and   malignant   proliferative   disorders   of  the   prostate   (Khosravi   et  al.,  2001; Hammersten  and  Hogstedt,  2001).  In  2006,  Nandusha  and  Co  correlated  insulin  profile parameters with prostate size and found that fasting serum insulin and insulin resistance levels were  significantly  higher in non-diabetic  BPH cases when compared  to the control values. Hyperinsulinemia ensures that fats are not mobilized from fat stores, resulting in obesity, while insulin resistance could lead to diabetes (Nandusha et al., 2006).

Obesity  (BMI≥30kg/m2)   is  the  result  of  imbalances  in  energy  intake  and   expenditure. Abdominal  obesity increases  the estrogen  to androgen  ratio  and may  increase  sympathetic nervous activity, both hypothesized to influence the development of prostate pathologies and severity  of  urinary  obstructive  symptoms  (Mongui  and  McVary,  2009).  Average  prostate weight has been shown to increase with increasing body weight, and that prostate volume is greater in obese and central obesity group than in normal subjects (Lee et al., 2006; Parsons et al., 2006).

Diabetes mellitus is characterized by impaired glucose metabolism. Type 2 diabetes mellitus has been shown to play a role in the etiology of prostate disorders (Stamatiou et al., 2009). The association  between  prostate  pathologies,  especially  BPH  and  diabetes  may  be  that,  both disorders share a common patho-etiology mechanism mediated by androgen-responsive growth factors (Stamatiou et al., 2009). Type 2 diabetes results in excessive presence of cholesterol in the blood-hypercholesterolemia.  Cholesterol is the backbone for steroid hormone biosynthesis.

It has been shown that serum total cholesterol levels are correlated with symptoms of  BPH (Ezeanyika  et al.,  2006a).  Studies  with  rats  have  shown  that  hypercholesterolemia  caused changes  in plasma  profile  of sex  steroids.  It  may  therefore  alter  prostate  morphology  by affecting the sex steroid axis and thus contribute to BPH (Mitropoulous et al., 2004; Parsons et al., 2008).

Studies  have  shown  that  metabolic  syndrome  usually  result  from  improper  nutrition  and

sedentary lifestyle.  High intake of dietary fats, and energy,  low intake of dietary fibre  and complex carbohydrates have been linked to prostatic disorders (Dagnelie et al., 2004). Dietary fat may alter androgen and IGF levels and promote cell proliferation in the prostate (Bosland,

2000). Ejike and Ezeanyika (2009) have shown that low dietary fibre and high animal fat may affect the prostate at all levels of human development-in uterus, childhood and adulthood, and lead to BPH.

1.3       Prevalence of prostate pathologies

Autopsy result show that BPH is present in 40% and 90% of men aged 50-60 years and 80-90 years respectively (Berry, 1984). The global prevalence among those aged 60 years and above exceeds 50% (Marberger et al., 2004). In the United States alone, BPH generated 1.1 billion dollars in health care expenditures and accounted  for over 4.4  million office visits, 117,000 emergency room visits and 105,000 hospitalization in the  year 2000 (Wei et al., 2005). More than 200,000 transurethral  resection of the prostate  for BPH are performed  annually in the United States (Graves and Gillum, 1997). Neslund et al. (2007) reported a prevalence of 42% and  Fernandez  et  al.  (2009)  reported  16.6%  prevalence  for  LUTS  in  Spain.  In  Tunisia, Horchani et al. (2007), reported prevalence of 26.4% for BPH symptoms and 16.1% for LUTS in the same male population. In Nsukka, Nigeria, a prevalence of 25.35% was reported for BPH symptoms (Ezeanyika et al., 2006b).

Prostate cancer is more prevalent in the developed countries probably because of feeding habit and it is well documented there than in the developing countries (Ezeanyika et al., 2006a). It is the most common cancer world-wide for males and the fifth most common cancer overall with an estimated 900,000 new cases diagnosed in 2008. According to American Cancer Society’s estimates in 2013, about 238,590 new cases may be diagnosed, with about 29,720 to die of prostate cancer in 2013.

1.3.1 Treatment/ Management option of Prostate pathologies

Treatment for prostate disorders may involve active surveillance,  surgery, radiation  therapy including, brachytherapy (prostate brachytherapy) and external beam radiation therapy, High- intensity focused ultrasound (HIFU), chemotherapy,  cryosurgery,  hormonal therapy, or some combination. The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option (Mouraviev et al., 2006). This may enter into the treatment decision.

Active surveillance

Active surveillance refers to observation and regular monitoring without invasive treatment. In the context of prostate  disease  this usually comprises  regular  PSA blood  test and prostate biopsies.  Active  surveillance  is  often  used  when  an  early  stage,  slow-growing  prostate disorders are suspected. However, watchful waiting may also be suggested when the risks of surgery, radiation therapy, or hormonal therapy outweigh the possible benefits. Approximately one-third of men that choose active surveillance for early stage tumors eventually have signs of tumor progression, and they may need to begin treatment within three years (Wu et al., 2004).

Hormonal therapy

Hormonal therapy uses medications or surgery to block prostate diseased cells from  getting dihydrotestosterone  (DHT), a hormone produced in the prostate and required for  the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate disorders like BPH,  cancer,  to  stop  growing  and  even  shrink.  However,  hormonal  therapy  rarely  cures prostate cancer because cancers that initially respond to hormonal  therapy typically become resistant after one to two years. Hormonal therapy is, therefore, usually used when the disease has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of the disease (Robson and Dawson, 1996).

Radical prostatectomy

Radical prostatectomy is effective for tumors that have not spread beyond the prostate ( Bill- Axelson et al., 2005) cure rates depend on risk factors such as PSA level.  However,  it may cause nerve damage that may significantly  alter  the quality of life of  the prostate  diseased survivor.

Transurethral resection of the prostate

Transurethral  resection of the prostate, commonly called a “TURP,” is a surgical  procedure performed  when  the  tube  from  the  bladder  to  the  penis  (urethra)  is  blocked  by prostate enlargement. In general, TURP is for benign disease and is not meant as definitive treatment for prostate cancer. During a TURP, a small instrument (cystoscope) is placed into the penis and the blocking prostate is cut away.

High intensity focused ultrasound (HIFU)

HIFU was first used in the 1940s and 1950s in efforts to destroy tumors in the central nervous system. Since then, HIFU has been shown to be effective at destroying malignant tissue in the brain, prostate, spleen, liver, kidney, breast, and bone (Gardner and Koch, 2005).

HIFU for prostate cancer utilizes high intensity focused ultrasound to ablate/destroy the tissue of the prostate. During the HIFU procedure, sound waves are used to heat the prostate tissue, thus destroying  the cancerous  cells.  In essence,  ultrasonic  waves  are  precisely focused  on specific areas of the prostate to eliminate the prostate cancer, with minimal risks of affecting other tissue or organs. Temperatures at the focal point of the sound waves can exceed 100°C (212  °F) (Gardner  and  Koch,  2005).  The ability to  focus the ultrasonic  waves  leads  to  a relatively low occurrence of both incontinence and impotence. (0.6% and 0-20%, respectively) (Uchida et al., 2006).

Palliative care

Palliative care for advanced stage prostate cancer focuses on extending life and relieving the symptoms  of  metastatic  disease.  Abiraterone  acetate  is  showing  some  promise  in  treating advance-stage prostate cancer. It causes a dramatic reduction in PSA levels and Tumor sizes in aggressive advanced-stage prostate cancer for 70% of patients. Chemotherapy may be offered to  slow  disease  progression  and  postpone  symptoms.  The  most  commonly  used  regimen combines the chemotherapeutic drug docetaxel with a corticosteroid such as prednisone. One study showed that treatment with docetaxel and prednisone prolonged life from 16.5 months for those taking mitoxantrone  and  prednisone to 18.9 months for those taking docetaxel + prednisone (Tannock et al., 2004). Bisphosphonates such as zoredronic acid have been shown

to delay skeletal complications such as fractures or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer (Saad et al., 2002).

Many other single agents have been shown to reduce PSA, slow PSA doubling times, or have similar effects on secondary markers in men with localized cancer in short term trials, such as pomegranate juice or genistein, an isoflavone found in various legumes (Pantuck et al., 2006).

1.3.2 Agents that relax smooth muscles

Prostatic  smooth  muscle  tone  is under  the  influence  of the  autonomic  nervous  system. It contracts  under the influence  of noradrenergic  sympathetic  nerves,  thereby  constricting  the urethra (Oesterling, 1995). Prostatic tissue contains high levels of both alpha-1 and alpha-2 adrenoreceptors.  A total of 98% of the alpha-1 adrenoreceptors  are  associated  with stromal elements  of the prostate  (Kobayashi  et al., 1993).  Alpha-1  receptor blockers  by induction, result in the relaxation of smooth muscles and the relief of bladder outlet obstruction enhancing urine flow. Alpha blockers used in the treatment of BPH are divided into selective and non selective alpha blockers. Some examples of  selective alpha blockers are prazosin, alfuzosin, tamsulosin, terazosin and doxazosin, while phenoxybenzamine,  nicergoline and thymoxamine are examples of non selective alpha blockers.

1.3.3 Agents that reduce prostate volume

Hormonal treatments find application in treatment targeted  at reduction in prostate  volume. Hormonal therapy involves the use of drugs that mimic hormones, to interfere with the cycle of testosterone production and action. Some of the methods used are;

Luteinizing  Hormone  Relaxing  Hormone  (LHRH)  analogues.  LHRH is released  by  the hypothalamus  and  it  interferes  with  the  feedback  mechanism  that  stimulates  and  controls testosterone production in the testis. LHRH analogues are chemically similar to LHRH. Some LHRH analogues  used  are leuprolide,  gosereline  and buserelin  (Garnick  and Glode,  1986, Peeling, 1989). They however cause an internal flare in testosterone concentration. Aberelix is a  gonadotrophin-releasing  hormone  antagonist  and  does  not  cause  the  flare  phenomenon (McLeod et al., 2001).

Anti-androgens

Anti-androgens inhibit the function of androgens at the cellular levels. When combined with castration,  maximal  androgen  blockade  (MAB)  or  complete  androgen  blockade  (CAB)  is

achieved.  They are  classified  according  to  their  chemical  structures  as  steroidal  and  non- steroidal anti-androgens. Non-steroidal anti-androgens do not lower serum testosterone but tend to increase it, whereas steroidal anti-androgens  significantly reduce both serum  testosterone and luteinizing hormone (LH) (Aus et al., 2005). The non steroidal anti-androgens currently available are nilutamide, flutamide and bicalutamide (Lundgren, 1987; Decensi et al., 1991). Cyproterone acetate or medroxy progesterone acetate are the steroidal anti-androgens used in hormonal therapy (Aus et al., 2005).

1.3.4 Medications that inhibit 5, alpha-reductase

Finasteride,  this acts predominantly  on the type-2  isoenzyme  of 5α-reductase  inhibiting  it. Finasteride reduces serum dihydrotestosterone levels by 85-90% (Roehrborn, 1998).

Dutasteride, this blocks both iso-enzymes of 5α-reductase (Foley and Kirby, 2003). It shows a

60-fold greater inhibition of type-1 isoenzymes than finasteride and is also active against the type-2 isoenzyme (Bartsch et al., 2002). The major side effects of hormonal therapy are loss of libido and impotence. Other physiological changes include hot flashes, altered and diminished body  hair,  gynaecomatsia,  osteoporosis,  muscle  atrophy,  anemia,  depression,  shortness  of breath, gastrointestinal upset, hepatotoxicity and wound infection (Aus et al., 2005)

1.3.5 Diet and prostate pathologies

Asians have the lowest incidence  and prevalence  rates of prostatic disease. However,  when these Asians relocate to high prevalence regions like USA, within their generation, the diseases become  common  and  often  resemble  that  of  the  local community  (Tsugane  et  al., 1990; Shimizu et al., 1991). This shows the place of diet in prostatic diseases.

Traditional  Asian  diets  are  rich  in  soy beans.  Soy is  known  to  be  rich  in  isoflavonoids. Genistein is the major isoflavone in soy and may help reduce the risk of prostate disorders by its  estrogenic  properties  or  by the  inhibition  of  5α-reductase  (Shirai  et  al.,  2002).  Other isoflavones are formonetin, biochanin and diadzein. Genistein and diadzein are also said to be capable of lowering androgen levels and increasing  sex  hormone binding globulin (SHBG) levels (Shirai et al., 2002). Isoflavones also  stimulate UDP-glucuronosyl  transferase  (which catalyzes  the  conjugation  of  steroid  hormones  to  UDP-glucuronic  acid)  activity,  thereby reducing the level of steroid hormones in the system by facilitating their excretion (Sun et al.,

1998).  They  inhibit  the  activities  of  the  enzyme  17β-hydroxysteroid   dehydrogenase  and

aromatatse (the former is the last of the two enzymes required for the formation of testosterone from dehydroepiandrosterone)  (Campbell and Kurzer, 1993; Keung, 1995).  Food substances containing these bioactive isoflavones are therefore useful in protecting against and managing prostate disorders. Furthermore, animal and in vitro studies show that retinoid and carotenes found in colored fruits and vegetables and lycopenes found  largely in tomatoes and tomato- based foods also have a protective role with respect to BPH pathogenesis (Edinger and Koff,

2006; Rohrmann et al., 2007).

Zinc intake and absorption is critical for the prostate especially during prostate disorders. Zinc is involved in various aspects of androgen metabolism and has been shown to reduce the size of the prostate and the symptoms in patients with prostate disorders. Zinc inhibits the activity of

5α-reductase and reduces prolactin binding to prostate receptors (Leake et al., 1984a and  b). However, zinc is known to reduce the absorption of copper, so zinc supplementation should rationally go with copper supplementation.

1.4. Botanical/ Phytotherapy

The use of plant extracts in the treatment of prostate disorders is becoming widespread (Gerber,

2002). It is estimated that therapeutic agents constitute approximately 50% of all  medicines prescribed  for BPH in Italy and almost 90% in Germany and Australia.  The  most popular phytotherapeutic  agents  are extracted  from  the seed  barks and  fruits  of  plants (Lowe  and Fagelman, 1999) and are preferred because they are seen as natural and do not cause adverse side effects that chemical agents are known to cause. Concerns about organ damage as often occurs with chemotherapy are also limited when botanicals are used. Some of the botanicals used in the treatment of prostate disorders that have received some scientific attentions are;

Saw palmetto

Saw palmetto or American dwarf palm (Serenoa repens or Sabal serulata) is one of the many plant materials  available for the treatment  of BPH (Tacklind  et al., 2009). The  liposterolic extract  of saw palmetto  berries  contain  capric,  caprylic,  caproic,  lauric,  palmitic  and oleic (fatty) acids and β-sitosterol  and stigmasterol  as the major  phytosterols.  It has three major activities that improve BPH symptomatology and inhibition of 5α-reductase (Deios et al., 1994; Weisser et al., 1996); inhibition of DHT binding to prostatic cells (El-Sheikh et al., 1988); and inhibiting  both  lipoxygenase  and  cycloxygenase  (arachidonic  acid  cascades)  (Breu  et  al.,

1992).

Nettles root

Extracts of stinging nettle (Urtica dioica) roots have been used extensively in the management of prostate pathologies (Krzeski et al., 1993). The mechanism of its action is still unclear, but it has been shown to inhibit prostate Na+/K+  ATPase thereby inhibiting binding of SHBG to its

receptor (Hirano et al., 1994; Hryb et al., 1995; Gansser and Spiteller, 1995).

African Palm tree

Extracts  of African plum (Pygeum africanum)  tree bark inhibit  the  proliferative  effects  of growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and insulin growth factor-1 (IGF-1) (Yablonsky et al., 1997) and antagonize the production of metabolites in the 5-lipoxygenase pathway (Gerber, 2002). Through these methods, the extracts are thought to reduce BPH (Wilt et al., 2002).

Rye pollen

Extracts of Rye grass (Secale cereale) pollen are thought to improve detrusor activity, reduce prostatic urethral resistance and inhibit 5α-reductase activity and androgen metabolism in the prostate.  By these  methods,  modest  alleviation  of BPH  symptoms  is  achieved  (Lowe  and Fagelman, 1999).

Pumpkin seed

Dried or fresh seeds of pumpkin (Curcubita pepo) contain phytosterols that act through  yet unclear  mechanism  to  relieve  BPH  symptoms  (Carbin  et  al.,  1990;  Schulz  et  al.,  1998). Pumpkin  seed  oil  has  also  been  shown  to  inhibit  testosterone  induced  hyperplasia  of the prostate (Gossell-Williams et al., 2006). Other plants such as South African star grass (Hypoxis rooperi), Cactus flower (Opuntia) and pine flower (Pinus) (Gerber, 2002), purple coneflower (Skaudickas  et al., 2009), flax seed lignin (Zhang et  al., 2008), Piper cubeba (Yam et al.,

2008), Bixa orellana (Zegarra et al., 2007), coconut oil (Arruzazabala et al., 2007) and Cuban royal palm (Noa et al., 2005) show some promise but have been studied in less details.

1.4.1 Moringa oleifera

Moringa oleifera belongs to the order/family,  Moringaceae.  It is the most widely cultivated species of a monogeneric family, the moringaceae that is native to the sub-Himalayan tracts of India, Pakistan, Bangladesh and Afghanistan. This rapidly-growing tree is also well known as;

Horseradish   tree,   Drumstick   tree,   Benzolive   tree,   Kelor,   Marango,   Mlonge,   Moonga, Mulangay, Ben oil tree. It is popularly known in Nigeria by the Igala-Hausa as ‘Geligedi’, Ibo as ‘Ikwe oyibo’ and ‘Oku ghare ite’ Yoruba as ‘Ewe ile’ and ‘Ewe igbale’.The tree is widely cultivated in many locations in tropics, it is a perennial plant. It is already an important crop in India, Ethiopia, the Philippines, and the Sudan. It is being grown in the West, East and South Africa, tropical Asia, Latin America, the Caribbean, Florida and the Pacific Islands. All parts of the moringa tree are edible and have long been consumed by humans. Many uses of moringa includes; biomass production, animal forage, biogas (from leaves), domestic cleaning (crushed leaves), blue dye (wood), fencing (living trees), fertilizer (seed-cake), foliar nutrient (juice from the leaves), gum (from tree trunks), honey (flower necter), honey and sugar cane juice-clarifier (powdered seeds), medicine (all plant parts), tannin for tanning hides (bark and gum), water purification (powdered seeds) (Fuglie, 1999). Moringa seed oil (yield 30-40% by weight), also known as Ben-oil, is a sweet non-sticking, non drying oil that resist rancidity. The oil has been used in salads, for fine machine lubrication, and in the manufacturing of perfume and hair care products  (Tsaknis  et  al.,  1999).  In  the  west,  the  powdered  seed  is  used  to  flocculate contaminants and purify drinking water (Olsen, 1987; Gassenschmidt et al., 1995), the seeds are eaten green, roasted, powdered and steeped for tea or used in curries (Gassenschmidt et al.,

1995).

1.4.1.1 Nutrition

Moringa trees have been used to combat malnutrition, especially among infants and  nursing mothers. It is a natural nutrition for the tropics. Leaves can be eaten fresh, cooked or stored as dried powder for many months without refrigeration, and with less nutritional value. Moringa leaves contain more vitamin A than carrots, more calcium than milk, more iron than spinach, more vitamins than oranges and more potassium than bananas. The protein quality of moringa leaves rivals that of milk and eggs (Fuglie, 2000).

1.4.1.2 Phytochemistry

Phytochemical  refers to only those chemicals  which may have an impact on health, or  on flavor,  texture,  smell,  or color  of the  plants,  but  are  not required  by humans  as  essential nutrients. Phytochemicals of moringa species reveal that the plant family is rich in compounds containing the simple sugar, rhamnose, and it is rich in a fairly unique group of compounds

called   glucosinolates   and  isothiocyanates   (Fahey  et  al.,  2001).   For  example,   specific components of moringa preparations that have been reported to have hypotensive, anticancer, and        antibacterial        activity        includes;         4-(4´-O-acetyl-α-L-rhamnopyranosyloxy) benzylisothiocyanate,         4-(α-L-rhamnopyranosyloxy)benzylisothiocyanate,         niazimicin,

Pterygospermin, benzylisothiocyanate,  and 4-( α-L-rhamnopyranosyloxy)benzylglucosinate. It is  also   rich  in  vitamins   and  minerals,   as  well  as  other  more  commonly  recognized phytochemicals such as carotenoids (including-6-carotene or pro-vitamin A) (Fuglie, 1999).

1.4.1.3 Disease treatment and prevention

The benefits for the treatment and prevention of disease or infection that may accrue  from either  dietary  or  topical  administration  of  moringa  preparations  (e.g.  extracts,  decoctions, poultices,  cream,  oils, emollients,  salves,  powders,  porridges)  are not quite  so well known (Palada, 1996). Even at that, moringa preparation have been cited in the scientific literature as having antibiotic , antitrypanosomal, hypotensive, antispasmodic, antiulcer, anti-inflammatory, hypocholesterolemic,  and hypoglycermic activities, as well as having considerable efficacy in water purification by flocculation, sedimentation, antibiosis and even reduction of schistosome cercariae  titer,  evaluation  of  a  variety  of   detoxification  and  antioxidant   enzymes  and biomarkers as a result of treatment with moringa or with phytochemicals isolated from moringa (Kumar and Pari, 2003).

1.4.1.4 Antibiotic activity

This is clearly the area in which the preponderance  of evidence-both classical scientific  and extensive  anecdotal  evidence  is  overwhelming.  The  identification  of  a  compound  called pterygospermin, is a compound which was reported, readily dissociated into two molecules of benzyl isothiocyanate (Narasimha-Rao and Kurup, 1953), the compound has antibiotic activity against H. pylori at concentration up to1000-fold lower than other plants which had been used in earlier studies against a wide range of bacteria and fungi (Galan et al., 2004)

1.4.1.5 Cancer prevention

Moringa species have long been recognized by folk medicine practitioners as having value in tumor    therapy   (Hartwell,    1971).    Compounds    of    these    plants;    4-(4´-O-acetyl-α-L- rhamnopyranosyloxy)          benzylisothiocyanate,          and          4-(α-L-rhamnopyranosyloxy) benzylisothiocyanate showed cancer preventive potential (Fahey et al., 2004). 4-(4´-O-acetyl-α- L-rhamnopyranosyloxy)  benzylisothiocyanate,  and    niazimicin, a phytochemical of Moringa

oleifera were shown to be potent inhibitors of phorbol ester (TPA)-induced Epstein-Barr virus early antigen activation in lymphoblastoid (Burkitt’s lymphoma) cells (Murakami et al.,1988). Studies also  showed  that niazimicin  also  inhibited  tumor promotion  in a  mouse two-stage DMBA-TPA tumor model (Murakami et al., 1998). Bharali and colleagues have examined skin cancer tumor prevention following ingestion of drumstick (moringa seed pod) extract.

1.4.2 Vernonia amydalina

Vernonia amygdalina is a member of the Asteraceae family. It is a small shrub that grows in the tropical Africa. Typically it grows to a height of 2-5cm. the leaves are elliptical and up to

20cm long with a rough bark (Ijeh and Ejike, 2011). Vernonia amygdalina is popularly known as bitter leaf in English because of its bitter taste. African common names includes; onugbu or olubu  (Igbo),  ewuro  (Yoruba),  Ilo  (Igala),  ityuna  (Tiv),  grawa  (Amharic),  etidot  (Ibibio), muluuza (Luganda), labwori (Acholi), olusia (Luo), and ndole (Cameroon) (Egedigwe, 2010; Kokwaro, 2009).

The leaves are dark-green colored with a characteristic odor and a bitter taste. The specie  is indigenous  to  tropical  Africa  and  is found  wild  or  cultivated  all over  sub-Saharan  Africa (Bosch et al., 2005). The leaves are eaten after crushing and washing thoroughly to remove the bitterness (Mayhew and Penny, 1998). All parts of the plant are pharmacologically useful. Both the roots and leaves are used in phyto-medicine  to treat  fever, hiccups, kidney disease and stomach discomfort,  among others (Gill, 1992;  Hamowia and Saffaf, 1994). It also showed antihelmintic  and anti-tumoriagenic  properties  (Abosi and Raseroka,  2003) as well as anti- tumorigenic properties (Izevbigie  et al., 2004). Research also confirmed that the leaf extract demonstrated  hypoglycemic  and  hypolipidemic  effects  in  experimental  animals  (Nwanjo,

2005).

Consequently,  Vernonia  amygdalina  extracts  and  isolated  chemical  constituents  have  been studied  for  their  potential  pharmacological  effects,  including,  induction  of  apoptosis  as determined  in cell  culture  and  animal  studies  (Sweeney  et  al., 2005;  Song et  al., 2005), enhanced chemotherapy sensitivity as with cancerous cells (Sweeney et al., 2005), inhibition of growth of growth signals of cancerous cells (Izevbigie et al., 2004; Opata and Izevbigie, 2006), suppression of metastasis of cancerous cells in the body by the inhibition of NFKB, an anti- apoptic transcription factors as demonstrated in animal studies (Song et al., 2005), reduction of estrogen level in the body by the suppression of aromatase activity, provision of antioxidant benefits  (Erasto  et al., 2007), enhancement  of  the immune  system (Sweeney et al., 2005),

decreased blood glucose by 50% compared to untreated diabetic animals in a study conducted using  streptozotocin-induced   diabetic   laboratory   animals   (Nwanjo,   2005)   and   in  vitro antihelmintic and antiparasitic properties (Ademola, 2011).

1.5 Study Rationale/Justification

The rate of prostate disorders is on the increase and asymptomatic in most cases. Hence, the need to investigate the use of natural products in its management or treatment. Medicinal plants have been of great help right from creation and have limited cases of threat like the synthetic drugs. Moringa oleifera  which is popularly called ‘miracle tree’  and Vernonia amygdalina, have been used in the treatments and management of various ailments. However, no scientific report is available regarding the traditional use of, especially Moringa oleifera in the treatment and management of prostate disorders. In view of this, there is a need to investigate the use of these plants in the treatment or management of prostate disorders.

1.6 Aim and objectives of the study

1.6.1 Aim of the study

This study is aimed at investigating the effects of Moringa oleifera and Vernonia amygdalina leaves on prostate pathologies (Benign Prostate hyperplasia, Prostatitis and Prostate cancer) in experimental rats.

1.6.3    Objectives of the Study

1.   To  determine  the  effects  of  aqueous  leaf  extract  of  Moringa  oleifera  on  some biochemical indices in albino rats.

2.   To determine  the effects of aqueous  leaf extract  of Vernonia  Amygdalina  on  some biochemical indices in albino rats.

3.   To determine the effects of the two extracts on lipid profile of rats.

4.   To compare the effectiveness  or potency of the two aqueous  leaf extracts on  some biochemical indices in albino rats.

5.   To determine the effectiveness of Moringa oleifera and Vernonia amygdalina extract on some biochemical indices in albino rat



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COMPARATIVE STUDY OF THE EFFECTS OF AQUEOUS EXTRACTS OF MORINGA OLEIFERA AND VERNONIA AMYGDALINA LEAVES ON SOME BIOCHEMICAL INDICES IN ALBINO RATS

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