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Suppression of Thermal and Chemical Nociception in Rats by Methanol Extract and its Sub-Fractions from Lantana camara.

Byline: Shabana Usman Simjee, Humera Perveen, Syeda Qamar Zehra, Anjum Ayub, Bina Shaheen Siddiqui and Sabira Begum

Summary: The traditional use of Lantana camara (Verbenaceae) is reported to include anti- nociceptive, antimicrobial, and immunosuppressant activity. To our knowledge no systematic study has been carried out on the anti-nociceptive activity of L. camara. The present study was designed to delineate the analgesic activity of L. camara extract and its fractions to elucidate the traditional belief in the painkilling effects. Experimental models employed were thermal and chemical-induced nociception assays. After initial screening of the methanol extract and its fractions prepared from the aerial parts of the plant, the dose of 50,100 and 200 mg/kg were selected and route of administration was i.p. The test samples were tested against a reference drug indomethacine (i.p. 5 mg/kg). The observations were made at 15, 30, 60, and 120 seconds following the administration of the samples or reference drug.

Experiments on naloxone antagonism were conducted to determine involvement of opioid receptors. Compared to concurrent controls, a significant anti-nociceptive activity was observed in methanol extract LC (ED50 50 mg/kg, P < 0.002) and its sub-fractions LCEA-AQ (ED50 50 mg/kg, P < 0.004), LCEA (ED50 100 mg/kg, P < 0.004) and LCEA-PEI (ED50 100 mg/kg, P two times the pre-drug average latency. Tail flick latency difference or mean increase in latency after drug administration was used to indicate the analgesia produced by test and standard drugs. Analgesia TFLD was calculated as follows:

Analgesia TFLD = signifies post drug tail flick latency - pre-drug tail flick latency

Acetic Acid-Induced Writhing in Mice

The method of [33] was employed with modifications in timing of observations in this experiment. Only active test samples were used in this writing test. Total of 42 mice were divided into seven groups (n=6) and pre-treated as follows: groups I, II, III and IV received test sample LC, LCEA-AQ, LCEA and LCEA-PEI respectively, group V received morphine (2 mg/kg), group VI which served as the control, received saline in appropriate volumes and group VII which served as the positive control received only acetic acid and no other treatment. After the 30 min pre-treatment time, each group was administered 0.7% of an aqueous solution of acetic acid (10 ml/kg) and the mice were then placed in transparent Perspex observation boxes for observation.

After 5 min lag period post- administration of acetic acid, the number of abdominal constrictions was counted for each mouse for 5 min and the count repeated twice at 15 min intervals, i.e. at 20 and 35 min. Observer was blind to the treatment each animal received. The percentage inhibition of constrictions for the extract- and indomethacin-treated groups was calculated.

Naloxone Antagonism of Antinociceptive Activity

This experiment was conducted employing seven groups of male and female mice (n=6). Only active extract and fractions were used in this experiment. Group I served as the control and administered sterile water only. Groups II, III, IV and V were treated with LC extract (520 mg/kg), LCEA- AQ (50 mg/kg), LCEA (100 mg/kg), LCEA-PEI (50 mg/kg), respectively. Morphine (4 mg/kg) was injected into groups VI and VII, while groups II-VI received naloxone (2 mg/kg), 10 min before their respective treatment. Hot-plate test was carried out in a similar manner as previously described with the reaction time being recorded at 0, 15, 30, 60 and 90 min after test samples and drug treatment.

Statistical Analysis

All data were expressed as the Mean +- S.E.M. Data was subjected to Students t-test. Results with P<0.05 were considered statistically significant.

Results and Discussion

The traditional uses of Lantana camara have been well described for a variety of medicinal purposes. However, not much of the scientific studies are done to validate its traditional use. The present study was designed to delineate the analgesic activity of the methanol extract of Lantana camara and its fractions to clarify the traditional belief in the painkiller effects of this plant in traditional medicine. Since the preliminary experiments conducted with the methanol extract of Lantana camara exhibited acute anti-nociceptive activity, therefore fractions of this extract were prepared to evaluate their effects on nociception. The experimental models used in this study employed chemical- and thermal-induced nociception. They were selected such that both centrally and peripherally mediated effects were measurable.

Table-1: Time course of the anti-nociceptive effect of methanol extract (LC) and its fractions in the tail withdrawal test (sec). Each value (mean +- S.E.M, n= 6) represents the time until the mice showed a tail withdrawal response.

###Tail Withdrawal Latency (sec)

###Treatment###0 min###15 min###30 min###60 min###120 min

###No treatment###2.0 0.35###3.33 0.4###3.6 0.29###2.90 0.17###2.51 0.09

###Water (10 ml/kg)###1.8 0.21###3.16 0.19###2.0 0.24###2.66 0.34###2.8 0.32

###Saline (0.5 ml)###3.33 0.36###2.51 0.22###2.0 0.24###3.07 0.14###2.0 0.24

Indomethacin (5mg/kg)###1.6 0.19###*6.3 0.53###8.3 1.07###8.5 0.85###8.9 0.70

###LC (50 mg/kg)###3.01 0.34###4.99 0.38###*5.08 0.50###6.55 0.51###7.97 0.66

LCEA-AQ (50 mg/kg)###2.50 0.31###3.22 0.36###5.74 0.39###5.97 0.11###6.91 0.17

###LCEA (100mg/kg)###3.75 0.40###5.46 0.27###6.58 0.39###7.0 0.23###7.73 0.29

LCEA-PEI (50 mg/kg)###1.98 0.29###4.90 0.42###5.76 0.29####6.38 0.26###6.52 0.34

LCEA-PES (200 mg/kg)###1.3 0.21###1.71 0.16###2.6 0.61###3.50 0.36###4.19 1.08

LCEA-ESol (200 mg/kg)###1.6 0.49###2.1 0.47###2.6 0.42###2.6 0.21###1.92 0.44

LCEA-EI (200 mg/kg)###2.76 0.31###3.75 0.38###4.35 0.46###4.35 0.51###5.26 0.39

LCEA-EAS (200 mg/kg)###2.0 0.51###3.10 0.51###2.6 0.80###3.8 0.94###2.3 0.98

LCEA-EAI (200 mg/kg)###2.6 0.33###2.0 0.36###3.60 0.25###2.6 0.49###2.97 0.85

Table-2: Time course of the anti-nociceptive effect of methanol extract (LC) and its fractions in the paw withdrawal test (sec). Each value (mean +- S.E.M, n= 6) represents the time until the mice showed a paw withdrawal response.

###Paw Withdrawal Latency (sec)

###Treatment###0 min###15 min###30 min###60 min###120 min

###No treatment###2.78 0.09###3.3 0.13###2.5 0.05###3.6 0.22###3.1 0.18

###Water (10 ml/kg)###2.8 0.07###3.0 0.26###2.6 0.09###2.3 0.18###3.1 0.44

###Saline (0.5 ml)###2.8 0.05###2.6 0.51###2.8 0.11###3.6 0.09###2.0 0.26

Indomethacin (5mg/kg)###2.8 0.13###*5.68 0.37###6.7 0.30###7.1 0.28###8.20 0.28

###LC (50 mg/kg)###2.0 0.00###4.90 0.60###*5.81 1.40###6.09 0.80###6.90 0.68

LCEA-AQ (50 mg/kg)###2.6 0.16###4.23 0.27###4.68 0.19###6.68 0.19###7.2 0.17

LCEA (100mg/kg)###1.57 0.09###4.76 0.13###5.90 0.33###6.38 0.45###7.02 0.30

LCEA-PEI (50 mg/kg)###3.2 0.10###5.09 0.42###*5.51 0.28###6.93 0.18###6.5 0.08

LCEA-PES (200 mg/kg)###3.2 0.33###4.3 0.66###4.16 1.02###5.16 0.79###5.13 1.02

LCEA-ESol (200 mg/kg)###2.6 0.16###2.0 1.23###2.8 0.96###2.6 1.07###3.0 0.81

LCEA-EI (200 mg/kg)###3.0 0.33###3.3 1.45###4.5 1.08###4.8 1.40###4.8 0.99

LCEA-EAS (200 mg/kg)###3.2 0.66###2.58 0.88###2.9 1.30###3.2 0.94###2.12 1.14

LCEA-EAI (200 mg/kg)###3.2 0.16###2.20 1.23###2.9 0.96###3.2 1.07###2.12 0.81

The thermally induced nociception models were used in this study to evaluate the activity of the test samples (Table-1 and 2) because they are the most commonly used stimuli for pain research. The heat-evoked flexion reflex has proven to be surprisingly good predictor of the analgesic potential of pharmacological compounds [34]. The thermal painful stimuli are also known to be selective to centrally-acting analgesic drugs. The thermally- induced nociception test has been found to be suitable for evaluation of centrally but not of peripherally acting analgesics [35].

In the present studies methanolic extract (LC) and its main fractions LCEA-AQ and LCEA and sub-fraction LCEA-PEI of the later fraction showed maximum anti-nociceptive activity at 120 min when compared with untreated animals and the values were found to be significant [F(4,29)= 6.72; P < 0.05]. In contrast the sub- fractions (LCEA-ES, LCEA-EI, LCEA-EAS, and LCEA-EAI) of LCEA-PEI were found inactive. The most potent activity was exhibited by the extract LC and its fraction LCEA in the paw-withdrawal test and LCEA-PEI in the tail-withdrawal test. There was a gradual increase in the anti-nociceptive activity in all active fractions and this effect reached maximal values at 120 min after administration. Comparing values obtained for reaction time of animals treated with the extract LC and its fractions and the control values both before and after treatment, it is clear that the LC, LCEA-AQ, LCEA and LCEA-PEI caused a considerable prolongation of latency times which indicates centrally mediated activity.

Since the thermal nociception assays reveal central activity therefore the acetic acid abdominal constriction method was also employed to elucidate peripheral effects of the test samples. The acetic acid- induced abdominal constriction method is very sensitive and able to detect antinociceptive effects of compounds and dose levels that may appear inactive in other methods like the tail-flick test [36, 37].

The test samples LC, LCEA-AQ, LCEA and sub-fraction LCEA-PEI were also found to decrease the number of acetic acid-induced abdominal constrictions in mice and the values were found to be significant [F(4,29)=15.92; P < 0.04]. The active samples also provided analgesia over the 40-mintues monitoring period of the study and the effects increased with time in most cases. The maximal percentage inhibition of constrictions for the LC (79.43 %) was observed at 50 mg/kg, during the first 5-10 min of monitoring (Table-3). The LCEA-AQ, LCEA and LCEA-PEI also exhibited significant (P < 0.04 for LCEA-AQ, LCEA and P < 0.05 LCEA-PEI) inhibition of abdominal constrictions, but the maximal percentage inhibition for these latter three samples was 70.29, 62.0 and 69.71% observed between 15 and 50 min of the study. The rest of the tested fractions did not exhibit anti-nociceptive activity.

The method has been associated with prostanoids in general, e.g. increased levels of PGE2 and PGF2a in peritoneal fluids [38], as well as lipoxygenase products [39, 40]. The results of the acetic acid-induced abdominal constriction test, strongly suggest that one of the mechanisms of action of the active test samples may be linked to lipoxygenases and/or cyclo-oxygenases.

Next we also studied naloxone antagonism in order to determine involvement of opioid receptors. The test samples at the doses tested, showed antinociceptive activity evident in all three nociceptive test models, signifying the presence of both central and peripherally mediated activities. The test samples which showed maximal increase in the reaction time in the hot-plate method were selected from this study. Results showed that the anti- nociceptive effects of the test samples did not antagonize by naloxone (2 mg/kg), whereas, anti- nociceptive activity of morphine (4 mg/kg) was significantly [F(6,41)=6.57; P < 0.05] lost by naloxone pre-treatment (Table-4). Reaction time values for the naloxone pre-treated group VI was found to be significantly (P < 0.05) lower than its counterpart group treated with only morphine.

Thus none of the active test samples showed lost of activity by naloxone antagonism which indicates that they are not acting through opioid receptors.

The methanol extract (LC), ethyl acetate phase (LCEA), aqueous phase (LCEA-AQ), and petroleum ether insoluble fraction (LCEA-PEI) from aerial parts of L. camara were analyzed by TLC on silica gel. After development using hexane-EtOAc 9:1 and 8:2 for LCEA and CHCl3-MeOH 95:5, 9:1 and 8:2 for LC and LCEA-PEI, the TLC plates were sprayed with ceric sulfate indicating the presence of several characteristic spots of terpenoids in LCEA and LCEA-PEI. UV active spots were also observed on TLC indicating presence of flavonoides and other aromatics.

To confirm these observations, the respective 1H NMR spectrum (in CDCl3 and CDCl3 + methanol-d4, respectively) of these fractions were recorded, and signals at d 0.80-1.18 and d 1.45-2.31 were assigned to methyl and methylene groups respectively while d 5.2-5.4 were characteristic of olefinic protons, d 3.0-3.2 corresponded to protons of oxymethinic carbon, and d 2.8 and 2.3 were attributed to allyl protons. These data are characteristic of pentacyclic triterpenoids, mainly those of oleanane/ursane skeleton [41], suggesting the occurrence of lantadenes and / or lantanolic acid derivatives, previously isolated from leaves of L. camara [42-44]. Although these compounds have been detected as major derivatives, one minor singlet at d 0.66 was observed and in association to multiplets at d 3.4 and 5.3 can be considered an indication of the presence of sterols [45], such as sitosterol/stigmasterol/ campesterol, previously isolated from L. camara leaves [46].

Along with these substances, fatty acid derivatives were also detected by the presence of a triplet at d 2.3 (J = 7.3 Hz), an intense broad singlet at d 1.2 which is characteristic of methylene groups and one deformed triplet at d 0.8 (J = 7.3 Hz), assigned to terminal methyl group in the aliphatic chain. Furthermore, several aromatic CH were also observed indicating the presence of flavonoids previously isolated from L. camara [8].

Table-3: Analgesic actions of methanol extract LC (Lantana camara) and its active fractions on acetic acid- induced writhing response. Each value represents the mean +- S.E.M. (n = 6).

###Treatment###Dose (mg/kg)###Average Writhing (mean+- S.E.M)###% Writhing###% Inhibition###T-Test

###Control###0.5ml of 0.7% Acetic Acid###35###100###-###P<0.7

Morphine hydrochloride (drug control)###2mg/kgi.p###52###14.8###85.14###P<0.001

###LC###50mg/kg###7.2###20.57###79.43###P<0.04

###LCEA-AQ###50mg/kg###10.4###29.71###70.29###P<0.02

###LCEA###50mg/kg###13.3###38###62###P<0.04

###LCE

###50mg/kg###10.6###30.28###69.71###P<0.04

###A-PEI

Table-4: Anti-nociceptive activity of the methanolic extract LC, its active sub-fractions extracted from Lantana camara Linn, and morphine and their antagonism by naloxone assessed by hot-plate test (paw withdrawal latency).

###Paw Withdrawal Latency (sec)

###Group###Treatment

###0 min###15 min###30 min###60 min###120 min

###I###Water (0.3 ml, Control group)###2.6 0.16###1.3 0.18###2.5###0.15###1.92 0.31###3.0###0.23

###II###LC extract (50 mg/kg) + Naloxone###2.0 0.07###4.25 0.16###5.08 0.07###6.89 0.24###7.681 0.24

###III###LCEA-AQ (50 mg/kg) + Naloxone###2.50 0.31###4.17 0.32###5.79 0.29###6.68 0.14###7.65 0.09

###IV###LCEA (100 mg/kg) + Naloxone###3.08 0.11###5.08 0.27###6.92 0.22###7.9 0.28###9.20 0.34

###V###LCEA-PEI (50 mg/kg) + Naloxone###2.45 0.16###4.50 0.36###5.76 0.15###6.88 0.25###7.52 0.34

###*

###VI###Morphine###3.21 0.22###6.76 0.52###8.90 0.33###10.38 0.55###14.72 0.73

###**

###VII###Morphine + Naloxone###2.85 0.21###5.09 0.42###6.51 0.39###6.0 0.28###5.5###0.14

The 1H NMR spectrum of LC (in CD3OD) showed more intense peaks at d 1.2 (br. singlet) d 0.8 (triplet, J = 7.2 Hz) and d2.3(triplet, J=2.3Hz) which are characteristic of fatty acid derivatives such as, palmitic and myristic acids, previously detected in L. camara [43]. In addition, minor signals at d 3.4-4.3 observed in both LC and LCEA-AQ (in pyridine-d5) indicated the occurrence of glucosyl compounds and sugars [5], such as maltose, glucose, and rhamnose previously obtained from L. camara [47]. This analysis suggested that the triterpenoids detected in the LCEA and LCEA-PEI were not observed in the LC and LCEA-AQ phase or could be present in very low concentration in the crude extracts.

Therefore, these fingerprints using TLC and NMR analysis indicated the presence of steroids, fatty acids, flavonoides and pentacyclic triterpenoids in less polar ethyl acetate phase (LCEA) and petroleum ether insoluble fraction (LCEA-PEI) while glycosides and sugars as major compounds in the polar methanol extract and aqueous fraction from aerial parts of L. camara.

Thus the phytochemical analysis indicated that the methanol extract LC and its polar fractions contain triterpenoids, flavonoids and fatty acids [8]. Among the class of compounds characterized in this extract and its fractions, flavonoids may be mainly responsible for the pharmacological activities since they are known to have antioxidant activities as well as analgesic and anti-inflammatory activities [48]. The flavonoids are also reported to treat many important common diseases, due to their proven ability to inhibit specific enzymes, to stimulate some hormones and neurotransmitters, and to scavenge free radicals [49, 50]. Studies have reported the modulation of GABAA receptor function by flavonoids [51, 52], which can explains that the anti- nociceptive activity of the active extract and its fractions might be due to its modulatory activity of GABAA receptor, since GABA is an inhibitory pathway which also controls the transmission of nociceptive signals.

In addition, the bioflavonoids have been reported to suppress COX-2 enzymes though the mechanism of this action is not fully understood [53], and attenuates the cold allodynia as well as hyperalgesia [54]. This could also be one of the mechanisms involved in suppression of nociception by the active fractions of Lantana camara used in this study.

Conclusion

In conclusion, this study has shown that the methanol extract of Lantana camara and its active fractions have antinociceptive activity in the model of nociception used in this study. This observed activity may be both peripherally and centrally mediated. At present, speculation can be made based on the obtained results and it is not possible to dissect out the most effective anti-nociceptive component of these samples because the mechanism of their action is unknown but calls for more detailed investigation. It is important to point out that studies are currently underway to isolate and characterize the active constituent(s) of the tested samples.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Author:Simjee, Shabana Usman; Perveen, Humera; Zehra, Syeda Qamar; Ayub, Anjum; Siddiqui, Bina Shaheen; Beg
Publication:Journal of the Chemical Society of Pakistan
Article Type:Report
Date:Aug 31, 2016
Words:5007
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