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Sur T K et a l / Acta Pharmac ol Sin 20 03 Feb; 2 4 (2): 18 7-192 Chine se Academ y of Sci encesht tp:/ /www.Chi naPh ar.c om Anti-inflammatory and anti-platelet aggregation activity SUR Tapas Kumar, BISWAS Tuhin Kanti2, ALI Liaquat3, MUKHERJEE Biswapati4 Department of Pharmacology; 2SN Pradhan Centre for Neurosciences, Dr BC Roy Postgraduate Institute of Basic Medical Sciences 244B, Acharya J C Bose Road, Calcut a 700020, India; 3Research Division, BIRDEM, 122 Kazi Nazrul Islam Avenue, Dhaka 1000, Bangladesh KEY WORDS placental extracts; inflammation; carrageenin; platelet aggregation; adenosine diphosphate
ABSTRACT
AIM: To find the anti-inflammatory and anti-platelet aggregatory activity of human placental extract (HPE, Placentrex).
METHODS: The HPE was studied for anti-inflammatory effect in Wistar rats on carrageenin, serotonin (5-HT),
and prostaglandin E (PGE ) induced edema in acute model and cotton pellet induced granuloma on sub-acute
model. Anti-platelet aggregation was studied against pr otection of adinosine diphosphate (ADP)-induced aggrega-
tion of human platelet through in vitro study. RESULTS: HPE showed positive results both in acute and sub-acute
models of inflammation. Highly significant (P<0.01) results were obtained against 5-HT induced acute inflamma-
tion and cotton pellet induced sub-acute inflammation in comparison with standard (diclofenac sodium) and control
(normal saline) drugs. The anti-inflammatory property of HPE in animal model was well supported with clinical
study of platelet aggregation. There was highly significant (P<0.01) inhibition of platelet aggregation with HPE at
diff erent doses against ADP. CONCLUSION: Our data suggest that human placental extract may be useful in
suppressing inflammation and platelet aggregation.
INTRODUCTION
man placental extract has corticotropin releasing factor The var iety of biological actions of human pla- (CRF)-like action[1]. Enzyme-linked immunosorbant cental extract (HPE) is a matter of increasing interest.
assay (E LISA) studies r evealed that human placental Recent research studies reveal that HPE is the rich re- cytotrophoblasts which expressed interleukin-8, a sour ces of var io us bio- active subst ances like known mediator of inflammation, was suppr essed by polydeoxyr ibonucleotides ( PDRN), RNA, DNA, peptides, amino acids, enzymes, tr ace elements, etc[1].
The current study was aimed to find the anti-in- Therapeutic properties in the treatment of patients with flammatory activity of HPE in both acute and sub-acute wounds have been described[2]. It is reported that hu- experimental models. Platelet aggregation is an impor- tant pathogenic marker of inf lammation. Hence, onerational approach in the research of anti-inf lammatory drugs is to search for compounds causing inhibitions 1 Supported by M/s, Albert D avid Ltd, Calcutta, India.
4 of platelet aggregation. Although there are some re- Correspondence to Dr MU KHERJ EE Biswapati.
ports of placental extract for their anti-platelet aggrega- tion activity[4,5] but the observations not correlated with Sur TK et al / Acta Pharmac ol Sin 20 03 Feb; 2 4 (2): 18 7-192 its anti-inflammatory activity. In the current research trically at 0 h and 3 h after carrageenin injection. The programme, anti-inflammatory effect of human placental tr eated drugs wer e administered intramuscular ly 1 h extract was observed in experimental animal model while platelet aggregation activity was studied in clinical cases.
5-HT-induced paw edema In this exper iment 0.1 mL of 5-HT (1 g/L) in ster ile saline was injected MATERIALS AND METHODS
into the sub-planter tissue of the right hind paw of rats.
Test drug Human placentas weighing between
The paw volume was measur ed plethysmometr ically 400-600 g collected at the time of full term spontane- before and after 30 min of the 5-HT injection[8,9] . HPE, ous deliver y were immediately placed under ice, then diclofenac sodium, and 0.9 % NaCl were administered the amniotic membr ane and umbilical cor d wer e removed, minced into small pieces and washed with cold normal saline. Aqueous extract with these pieces landin E (1 mg/kg) was administered into the sub-planter of placenta was prepared, sterilized, and sealed in am- region of the right hind paw of rats, in accordance with pules (2 mL) under inert condition. The extract 1 mL the method of Willis and Cornelsen[10]. The paw vol- in the ampule was derived from 0.1 g of placenta. This ume up to the ankle joints were measured plethysmo- extract contains protein ( 0.95 g/L), DNA (2.8 mg/L), metrically before and after 30 min of the prostaglandin RNA (1.6 mg/L), Na+ ion (27.9 mmol/L), K+ ion (3.07 mmol/L), and Cl– ion (15.1 mmol/L).
Sub-acute inflammation Sub- acute inflamma- Acute toxicity (LD )
tion was produced by cotton pellet induced granuloma to evaluate the therapeutic dose as well as for screening in rats[11]. Sterile cotton (15±1) mg was implanted sub- of the CNS toxicity. HPE was administered f or this cutaneously bilaterally in axilla under ether anesthesia.
purpose at 0.4, 0.5, 0.6, 0.7, 0.8 , and 0.9 mL per 20 g The treated drugs were administered for consecutive 6 of mice in intra peritoneal route. The studies were car- d in the same dose as mentioned earlier. The animals wer e sacrificed on d 7. The gr anulation tissues with Animals Male Wistar rats weighing 150-180 g
cotton pellet were dried at 60 °C overnight and then the were used for present research programme. They were dr y weight was taken. The weight dif ferences were housed in groups under 12:12 h regime (lights on from considered as the weight of granulation f ormation.
7:00 h to 19:00 h) at (23±2) °C prior to the experiments.
Platelet aggregation study
They were supplied pellet diet and water ad libitum.
Selection of subject Total 15 volunteers of ei- Drugs Carrageenin (Sigma), serotonin hydrochlo-
ther sex were selected from the medical out patients’ ride (Sigma), prostaglandin E (Sigma), and adenosine department of Bangladesh Institute of Research and Re- diphosphate (Sigma) were used in this study.
habilitation on Diabetes, Endocrine & Metabolic Disor- Anti-inflammatory activity
ders (BIRDE M), Dhaka, Bangladesh. A careful drug Acute inflammation Acute paw edema was in- history was taken from the subjects. Patients not re- duced in groups of ten rats, each using three diff erent ceiving for last two weeks the dr ugs like aspir in, experimental models. The rats were deprived of food sulf inpyr azone, chlor pr omazine, amitr iptyline, for 24 h before the induction of inflammation, but wa- furosemide, penicillin and its derivatives, dextran, which ter was allowed ad libitum. The HPE was adminis- interfere with the platelet aggregation activity, were se- ter ed at dose of 300 mg/kg intr amuscular ly[ 6] .
lected for the present research programme.
Diclofenac sodium (10 mg/kg, im) and 0.9 % NaCl (5 Collection of blood Specimens of blood samples mL/kg, im) were used as reference drugs. After each were collected using 3.2 % sodium citrate at the ratio 1: treatment paw volume of the animals were measured 9 with the blood in plastic container with minimum trauma or stasis at the venipuncture site. Testing was per formed 30 min after venipuncture at the r oom flammation was induced by carrageenin according to the model of Winter et al[7]. For this purpose 0.1 mL of Preparation of plasma Samples of blood and 1 % suspension of carr ageenin in normal saline was anticoagulants were gently inverted up and down, avoid- injected into the sub-planter tissues of right hind paw in ing shaking. Platelet rich plasma (PRP) was pr epared rats. The paw volume was measur ed plethysmome- by centrifuging at 100×g under 4 °C for 15 min. PRP Sur T K et a l / Acta Pharmac ol Sin 20 03 Feb; 2 4 (2): 18 7-192 thus prepared wer e collected by caref ul pipetting in a Acute inflammation From the study it was ob- sterile polypr opylene tube and closed. Platelet poor served that there was significant (P<0.01) inhibition of plasma (PPP) was prepared by centrifuging at approxi- paw edema in the animals treated with HPE both on mately 2400×g for 20 min. PPP was collected in a carr ageenin (54. 3 %) and PGE (39. 7 %) induced inflammation. These results are almost same as in the Study methods of platelet aggr egation The case of diclofenac sodium ( 57.1 % and 44.4 % aggr egation was measured on a dual channel Chr ono- respectively) treated group. However, the rate of inhi- L og Optical Platelet Aggr egometer (Chrono- Log bition (P<0. 01) of edema in 5-HT induced acute in- Cor poration, Havertown PA 19083-4691) at constant flammation was even better (49.0 %) than diclof enac stirring of 1200 rpm (1000 rpm in 50 Hz Units) and sodium (39.4 %) treated group (Tab 1).
electr onically controlled temperature (37±2) °C. The Sub-acute inflammation In cotton pellet induced light tr ansmission was set at 0 % with PRP and at sub-acute inf lammation model, there was highly sig- 100 % with PPP[10]. Aggregation was induced with nificant (P<0.01) decrease of the weight of granuloma aggregating agent ADP at a concentration of 1 mmol/L.
tissue (39.5 % ) in HPE tr eated gr oup. However, the HPE was added at different doses of 2.5, 5, 10, and 20 rate of inhibition of granuloma tissue weight in diclofenac µL/mL, 5 min before addition of ADP.
sodium treated group (52.1 %) was found to be better Statistical analysis T he results of animal ex- periments were analysed by unpaired Student’s t test.
Anti-platelet aggregation activity Results of Paired t test method was applied for the analysis of the platelet aggregation were expressed as a percent of ag- gregation at a given time interval (5 min) from reagentaddition. Cent per cent aggregation was defined as the differences between the 0 % baseline (PRP) and 100 % Acute toxicity (LD )
baseline (PPP). Highly significant responses (P<0.01) of anti-platelet aggr egation were observed with all the observed that the HPE is safe upto 45 mL/kg body weight doses of HPE . T her e wer e 83. 9 % , 76 . 6 % , Anti-inflammatory activity
59.2 %, and 60.2 % aggregation of platelet with HPE atthe doses of 2.5, 5, 10, and 20 µL/mL of plasma (PRP) Tab 1. Effect of human placental extract (HPE) and diclofenac sodium on carrageenin induced rat paw edema. Mean±SD.
n
=10. cP< 0.01 vs control.
Experimental model Paw volume Paw volume Tab 2. Effect of human placental extract (HPE) and diclofenac sodium on sub-acute inflammatory model in rat. Mean±SD.
n
=10. cP< 0.01 vs control.
granuloma granuloma Inhibition/% granuloma Inhibition/% tissue/mg tissue/mg tis sue/mg Sur TK et al / Acta Pharmac ol Sin 20 03 Feb; 2 4 (2): 18 7-192 Tab 3. Effects of human placental extract (HPE) against
observed after HPE treatment (Tab 1) on carrageenin- ADP-induced platelet aggregation in human PRP.
induced paw edema in r ats may be mediated through Mean±SD. n=10. cP< 0.01 vs control.
either any of these mediators alone or in combination.
Hence, HPE was fur ther studied against paw edema Treatment groups and dose Platelet aggregation induced by individual agent like 5- HT or PGE .
5-HT is present in mast cells and is consider ably more potent than histamine in increasing vascular permeabil- ity in r ats[16]. As ther e was considerable r eduction (49.0 %) of inflammation in 5-HT pre-treated r ats by application of HPE, it might be conjectured that the in- hibitory action was 5- HT mediated. Pr ostaglandins (PGs) biosynthetic pathway or the cyclooxygenase (COX) activity of the enzyme is the site of action of non-steroidal anti-inflammatory drugs or NSAIDS[17,18].
Diclof enac sodium is a widely used potent NSAI DS with pronounced analgesic and anti-pyretic activity. It is used mainly for long term symptomatic treatment ofrheumatoid arthr itis, osteoarthritis, and ankylosing spondylitis[19,20]. Therefore, diclofenac sodium was se- lected in this study as positive control (Tab 1, 2). Henceit may be assumed that HPE exhibits their anti-inflam- matory responses either through inhibition/inactivation of chemical mediators or by dir ectly modulating PGproduction by suppression of COX. It has been recog- nized recently that mammalian cells explain two forms of COX activity. COX-1 is the major form present inplatelets, while COX-2 is only found in elevated levels in inflammatory exudates[20,21]. The action of HPE on Fig 1. Effect of different doses of HPE for anti-platelet ag-
PGE induced edema (Tab 1) explains that it may modu- gregation activity.
late PGs production by inhibition of COX.
The sub- acute anti-inflammatory activity of HPE was studied by investigation of its inhibitory ef fect on respectively with respect to 100 % PPP control (Tab 3, the granuloma formation (Tab 2). Cotton pellet granu- loma is a model of non-immunological type of inflam- DISCUSSION
mation mediated by the activation of the chemical me- Inflammation covers a series of reparative and diators of inflammation, mostly kinins[23]. T he action protective responses in tissue injury, whether caused of kinin involves the activation of two membr ane by infection, auto-immune stimuli or mechanical injury.
receptors, B and B . B -receptor plays an important Several classes of compounds such as plasma proteins, role in inflammatory pr ocesses[24,25]. In this present re- vasoactive amines, tissue digestive enzymes, biologi- search programme highly signif icant (P <0. 01) result cally derived oxidant and eicosanoids are all associated was obtained with HPE in cotton pellet induced sub- with inflammatory response[13,14]. Most of all investiga- acute inflammation model indicating that it may act by tors have reported that inhibition of carrageenin-induced the way of inhibiting the B -receptor.
inflammation in rats is one of the most suitable test pro- Platelets are essential for nor mal haemostasis.
cedure to screen anti-inflammatory agents[9]. The de- Activation of the clotting cascade by trauma results in velopment of car rageenin-induced edema is bi-phasic, platelet activation, which is followed by aggregation.
the first phase is attributed to the release of histamine, The major COX metabolite in platelets is thromboxane 5-HT, and kinins, while, the second phase is r elated to A (TXA ), which is capable of initiating aggr egation.
the release of prostaglandins[7,15]. The inhibitory action NSAIDS inhibit TXA production and thus inflamma- Sur T K et a l / Acta Pharmac ol Sin 20 03 Feb; 2 4 (2): 18 7-192 tion[26,27]. The aggregation of human platelets induced rats . Acta Pharmacol Sin 2001; 22: 1113-6.
by ADP was used[12] to study the anti-platelet effect of Winter CA , Ris ley EA, Nuss CW. Carrageenin-induced HPE (Tab 3). T here was 84 %±13 % aggregation of oedema in hind paw of the rats as an assay for anti-inflamma-tory drugs. Proc Soc Exp Biol Med 1962; 111: 544-7.
platelet against ADP with a dose of 2. 5 µL/mL HPE Kalbhen D A, Smalla HD. Pharmakologis che s tudies zur which gradually decreased (77 %±16 % f or 5 µL/mL) antiphlogistischen wirkung von pentos anpolysulfat in with the increase in dose, r eaching minimum (59 %± kombination mit metamizol. Drug Res 1977; 27: 1050-7.
33 %) with a dose of 10 µL/mL. There was no appre- Vogel HG, Vogel HW. In: Drugs dis covery and evaluation.
ciable change on f urther incr ease of the dose (60 %± 14 % for 20 µL/mL). ADP is contained within the 10 Willis A L, Cornelsen M. Repeated injection of prostaglan- din E in rat paws induces chronic swelling and a marked platelet in storage organelles and released from the platelet decrease in pain threshold. Prostaglandins 1973; 3: 353-7.
during formation of the primary haemostatic plug and 11 Penn GB, As hford A. The inflammatory respons e to im- thereby induce further platelet aggregation[28,29]. There plantation of cotton pellets in the rat. J Pharm Pharmacol ar e so many activation pathways leading to platelet aggregation. PGs and 5-HT are considered as the ma- 12 O’Brien J R. Platelet aggregation: some res ults from a new jor chemical mediators of platelet aggregation[30,31]. The method of study. J Clin Pathol 1962; 15: 452-5.
13 Larsen GL, Henson PM . Mediators of inflammation. Ann clinical study of platelet aggregation reflects that HPE can either inhibit PGs synthesis pathway or 5-HT release.
14 Brooks PM, Day RO. Nonsteroidal anti-inflammatory drugs: These data indicate that the anti-inflammatory ef- differences and similarities. N Engl J Med 1991; 324: 1716- fect of HPE might be mediated through the suppression of chemical mediators. Further experiments are needed 15 Clarke G D , Macphers on IS , P etrone G , S pangler RS .
to confirm the mode of action of anti-inflammatory and Antinoceptive effects of non-s teroidal anti-inflammatorydrugs in a rat model of unilateral hind paw inflammation. Eur J Pharmacol 1994; 257: 103-8.
16 Fuller RW. Pharmacology of central serotonin neurons. Ann ACKNOWLEDGEMENTS Authors are thankful to M/
s, Albert David Limited, Calcutta for the financial sup- 17 Vane J, Booting R. N ew insights into the mode of action of port of the resear ch progr amme. Sincere thanks are anti-inflammatory drugs. Inflamm Res 1995; 44: 1-10.
also due to the Head of the Department of Pharmacology, 18 Willoughby DA. Effects of prostaglandins PGF2α and PGE1 on vascular permeability. J Pathol Bacteriol 1998; 96: 381-7.
University College of Medicine, Calcutta and to the tech- 19 Todd PA, S orkin EM. D iclofenac sodium, a re-appraisal of nical staffs of the department of pathology and research its pharmacodynamic and pharmacokinetic properties, and division BI RDEM, Dhaka, Bangladesh and Director, therapeutic efficiency. Drugs 1988; 35: 244-85.
Central Drug Laboratory, Calcutta for various help.
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