Effect of D-004, a lipid extract from the Cuban royal palm fruit, on atypical prostate hyperplasia induced by phenylephrine in rats.
OBJECTIVE
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that results in obstructive lower urinary tract symptoms. Saw palmetto (Serenoa repens), the dwarf American palm (Arecaceae family), is commonly used to treat BPH. The Cuban royal palm (Roystonea regia) also belongs to the Arecaceae family, and 200-400mg of D-004, a lipid extract from its fruits, administered orally for 14 days has been shown to prevent testosterone- but not dihydrotestosterone-induced prostatic hyperplasia in rats. D-004 (125-250 microg/mL) added to preparations of rat vas deferens caused a marked, dose-dependent and significant inhibition of noradrenaline-induced smooth muscle contraction, a response mediated through alpha(1)-adrenoceptors, and was more effective in these respects than Saw palmetto. However, the in vivo effects of D-004 and Saw palmetto on the hypertensive response induced by noradrenaline were modest (albeit significant), and neither treatment affected resting blood pressure or heart rate in rats. The differential effects of D-004 in in vitro and in vivo models could be related to a differential affinity for adrenoceptor subtypes or to different bioavailabilities in vascular and urogenital targets. Phenylephrine injected into rodents induces prostatic hyperplasia with all the characteristic morphological changes of the condition but does not result in enlargement of the prostate. Therefore, this phenylephrine-induced change in rat prostate tissue is called atypical prostatic hyperplasia. It serves as an in vivo model of prostatic hyperplasia induced by stimulation of alpha(1)-adrenoceptors. The objective of this study was to determine whether D-004 can inhibit induction of atypical prostatic hyperplasia by phenylephrine in rats.


METHODS
Rats were randomly distributed into five groups (ten rats/group). One group was a negative control and received oral vehicle only. The other four groups were injected subcutaneously with phenylephrine (2 mg/kg): of these groups, one was a positive control receiving the vehicle, and the other three groups were treated with D-004 or Saw palmetto (both 400 mg/kg) or tamsulosin 0.4 mg/kg. All active treatments were given orally for 28 days. After completion of treatment, rats were placed unrestrained in metabolic cages and micturition studies were performed. The rats were later killed and their prostates removed and weighed. Prostate samples were processed for histological study, with histological changes being assessed according to a scoring system. Bodyweight was measured at baseline and at weekly intervals.


RESULTS
Histological examination of positive control rats revealed features of atypical prostatic hyperplasia, with piling-up, papillary and cribiform patterns and budding-out of epithelial cells. Micturition assessment revealed that phenylephrine significantly lowered both the total volume of urine in 1 hour and the volume per micturition; the latter was considered the main efficacy variable. D-004 and Saw palmetto extracts significantly prevented this reduction in volume per micturition by 70.5% and 68.6%, respectively, while tamsulosin totally abolished the reduction in micturition induced by phenylephrine (100% inhibition). Tamsulosin, D-004 and Saw palmetto significantly reduced the histological changes of atypical prostatic hyperplasia induced by phenylephrine by 73.1%, 61.2% and 50.0%, respectively.


CONCLUSIONS
Administration of D-004 resulted in marked and significant prevention of phenylephrine-induced impairment of micturition and histological changes in rat prostate. These findings indicate that, in vivo, D-004 effectively opposes these responses to phenylephrine, which are mediated through urogenital alpha(1)-adrenoceptors. In this respect, D-004 was moderately more effective than Saw palmetto, a phytotherapeutic standard used to treat BPH, but less effective than tamsulosin, a selective alpha(1A)-adrenoceptor antagonist.
Arruzazabala
M L
ML
Center of Natural Products, National Center for Scientific Research, Havana City, Cuba. clinica@enet.cu
Más
R
R
Molina
V
V
Noa
M
M
Carbajal
D
D
Mendoza
N
N
D000818:Animals; D028023:Arecaceae / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005638:Fruit / Q000737:chemistry; D008297:Male; D010656:Phenylephrine / Q000737:chemistry; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use*; D011470:Prostatic Hyperplasia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
C504503:D 004 extract; D010936:Plant Extracts; D010656:Phenylephrine