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Piplartine, an amide alkaloid from Piper tuberculatum, presents anxiolytic and antidepressant effects in mice.

Abstract

In the present work, we studied the effects of piplartine (PIP), an amide alkaloid isolated from the roots of Piper tuberculatum (Piperaceae), in the elevated plus maze, open field, rota rod, pentylenetetrazole (PTZ)-induced seizures, and forced swimming tests, in mice (Swiss, male, 25 g) to assess anxiolytic, sedative, muscle relaxant, anticonvulsant and antidepressant effects, respectively. Results showed that PIP (50 and 100 mg/kg, i.p.), similarly to diazepam, significantly increased not only the number of entrances (100% and 66%, respectively) but also the time of permanence in the open arms (104% and 199%, respectively), indicating that PIP presents an anxiolytic activity. Both effects were completely blocked by the previous administration of flumazenil what suggests the involvement of benzodiazepine type receptors. In the open field test, although PIP did not alter the number of crossings, it significantly increased grooming (103% and 119%) and rearing (60% and 23%), at the doses of 50 and 100 mg/kg respectively, as compared to controls. However, in the rota rod test, PIP was devoid of effect. Although in the PTZ-induced convulsion test, PIP did not alter the latency time for the onset of the first convulsion, as compared to controls, it significantly reduced in 58% and 60%, respectively, the animal's latency time to death. Furthermore, a significant and dose-dependent decrease in the immobility time, as evaluated by the forced swimming test, was observed after PIP administration (41% and 75% decrease, at the doses of 50 and 100 mg/kg, respectively), suggesting an antidepressant effect, similarly to that observed with imipramine, a classical antidepressant drug used as standard. In conclusion, we showed that PIP presents significant anxiolytic and antidepressant activities, making this drug potentially useful in anxiety and depression.

[c] 2007 Elsevier GmbH. All rights reserved.

Keywords: P. tuberculatum; Anxiolytic activity; Antidepressant activity; Piplartine

Introduction

Studies with plants from the Piperaceae family have shown a great diversity of secondary metabolites with biological activities (Navickiene et al., 2003; Navickiene et al., 2000). Among these metabolites, are lignanes, neolignanes, terpenes, propenylphenoles, chalcones, flavones, benzopyranes and amides. Amide alkaloids constitute characteristic metabolites of the Piperaceae family, and can be classified as isobutyl, pirrolydine, pirydonil and piperydines.

In some Northeast Brazil communities, the species P. tuberculatum, popularly known as "pimenta longa" and "pimenta darta", is largely used in folk medicine as a sedative and antidote for snake bite. In other communities, the fruits are used as a food spice with beans. It has been shown that amides isolated from P. tuberculatum have also a potent antifungic activity (Navickiene et al., 2000, 2003; Vasques et al., 2002). The Piperaceae family comprises four genera, represented by over 1000 species, along tropical and subtropical distributions. Plants of the genus Piper have been valued for their organoleptic, medicinal and pesticidal properties. The special organoleptic properties of the Piperaceae family have resulted in black pepper, prepared from the dried fruit of P. nigrum. The amide-type alkaloids piperine and piperylin have been held responsible for the sharp pungent taste of the spice, while pellitorine contributes to its aroma. Several studies suggested that piperamides could have insecticidal potential, and P. tuberculatum extracts have been shown to be the most active among 12 extracts prepared from neotropical Piper species against mosquitoes, earwigs and white grubs, as compared to P. nigrum and P. guineensis.

A recent work (Scott et al., 2004) showed that extracts from three species of the Piperaceae family, P. nigrum, P. guineensis and P. tuberculatum, were efficacious against insects from five orders. All three species contain isobutyl amides, plant secondary compounds that act as neurotoxins in insects. Among Piper species, one of the most studied is Piper methysticum. The P. methysticum extract, also known as kava extract, presents as its main bioactive constituents kava-lactones, also referred as kava-pyrones. Kava-lactones are thought to have anti-anxiety, analgesic, muscle relaxing and anti-convulsant effects. Although the literature is plenty of studies on the biological properties of kava extracts, mainly those related with its central effects, almost none is found on P. tuberculatum extracts or their isolated constituents. Thus, the objectives of the present work was to study the behavior and central effects of piplartine, an amide-type alkaloid isolated from the roots of P. tuberculatum, attempting to elucidate its mechanism of action.

Materials and methods

Animals

Male Swiss mice (25 g) were obtained from the animal house of the Federal University of Ceara, Brazil. They were maintained in a room with a controlled temperature of 22[+ or -]2[degrees]C, and a 12 h light/dark cycle with free access to food and water. Fifteen animals per group were used, and all the experiments were performed according to the Guide for the Care and Use of Laboratory Animals, of the US Department of Health and Human Services, Washington, DC (1985).

Drugs

Atropine sulfate, scopolamine hydrochloride, oxotremorine and pilocarpine sulfate were purchased from Sigma Chemical Co. (USA), and diazepam (10 mg/mL) was purchased from Uniao Quimica, Brazil. All other drugs were of analytical grade.

Plant material and isolation of piplartine

The roots of P. tuberculatum were harvested on the campus of the Federal University of Ceara (UFC), Fortaleza, Brazil. A voucher specimen (no. 34736) has been deposited at the Prisco Bezerra Herbarium, of the Biology Department of the same University. For the isolation of piplartine, 420 g of ground roots of P. tuberculatum were macerated with a mixture of petroleum ether/ethyl acetate 1:1 (1.5 L) for 24 h (three times). The solvent mixture was rotaevaporated under reduced pressure to yield a yellowish solid (13.24 g), which gave 4.35 g of piplartine, after crystallization in MeOH. Piplartine, [syn. Piperlongumine, N-(3,4,5-trimethoxy-cinnamoyl)-[[DELTA].sup.3]-piperidin-2-one], m.p. 122.2-122.6[degrees]C (Lit. 128-130 and 124[degrees]C) (Braz-Filho et al., 1981), was characterized particularly by uni- and bidimensional NMR analysis.

Pharmacological testing

Elevated plus maze

The plus maze for mice (Lister, 1987) consisted of two perpendicular open arms (30 x 5 cm) and two closed arms (30 x 5 x 25cm) also in perpendicular position. The open and closed arms were connected by a central platform (5 x 5 cm). The platform and the lateral walls of the closed arms were made of transparent acrylic. The floor was made of black acrylic. The maze was 45 cm above the floor. After treatment, the animal was placed at the center of the plus maze with its nose in the direction of one of the closed arms, and observed for 5 min, according to the following parameters: number of entries in the open arms, and time of permanence in the open arms. The time of permanence measures the time spent by the animal in the open and closed arms. Anxiolytic compounds reduce the natural animal's aversion to the open arms, and promote the exploration thereof. On the other hand, the forced or voluntary passages of the animal into the open arms of the EPM are associated with hormonal and behavioral changes, indicative of increased anxiety. Diazepam (1 mg/kg, i.p.) was used as a positive control for the anxiolytic effect.

Open field test

The open field area was made of acrylic (30 x 30 x 15 cm) with transparent walls and black floor, divided into nine squares of equal areas. The open field was used to evaluate the exploratory activity of the animal for 5min (Archer, 1973). The observed parameters were: number of squares crossed by the animal (with the four paws) and numbers of grooming (stereotyped behavior) and rearing (vertical exploratory activity).

Rota rod test

For the rota rod test, the animal was placed with the four paws on a 2.5-cm-diameter bar, 25 cm above the floor, which was turning at 12 rpm. For each animal, the number of falls (up to three falls) and the time of permanence on the bar for 1 min were registered (Dunham and Miya, 1957).

Forced swimming test

This test is the most widely used and recognized pharmacological model for assessing antidepressant activity, and was employed according to that described elsewhere (Porsolt et al., 1977, 1978). The development of immobility, when mice are placed in an inescapable cylinder filled with water, reflects the cessation of persistent escape-directed behavior. Briefly, mice had a swimming-stress session for 15 min (pre-test), 24 h before being individually placed in glass cylinders (height: 25 cm; diameter: 10 cm; and 10 cm filled with water at 24[+ or -]1[degrees]C) for 5 min (test). A mouse was judged to be immobile when it ceased struggling and remained floating motionless on the water, making only small movements necessary to keep its head above the water surface.

PTZ-induced seizures

The PTZ-induced seizures are similar to the symptoms observed in the absence seizures (petit mal epilepsy), and drugs useful in the treatment of this type of epilepsy also suppress PTZ-induced seizures (Marescaux et al., 1984). In the last day of treatment, all animals received a single injection of PTZ (80 mg/kg, i.p.). The latency for the first convulsion, the latency to death and the percentage of death after PTZ administration were the parameters studied in the experiment.

Statistical analysis

Results were expressed by means[+ or -]SEM and analyzed by analysis of variance (ANOVA) and Student-Newman-Keuls as the post hoc test. Results were considered significant at p<0.05.

Results

In the elevated plus maze test, our results show (Table 1) that similarly to diazepam which increased the time spent in the open arms by 325% (q = 21.025 at p<0.001), PIP also increased this parameter. The effect was dose-dependent and, at the doses of 50 and 100 mg/kg, it increased the time spent in the open arms by 104 (q = 6.212 at p<0.001) and 199% (q = 12.440 at p<0.001), respectively. Furthermore, significant increases in the number of entrances in the open arms were also observed, after administration of PIP at both doses, as compared to controls (100% and 66% at the doses of 50: q = 5.335 at p<0.01 and 100 mg/kg: q = 3.593 at p<0.05, respectively). As expected, an increase of 153% in the number of entrances in the open arms was observed with diazepam. Interestingly, while flumazenil, a benzodiazepine antagonist, did completely reverse PIP effects on both parameters, its blockade on the diazepam effect was only partial.

In the open field test (Table 2), although PIP did not alter the number of crossings, it significantly increased both grooming (103% and 119%) and rearing behavior (60% and 23%), as compared to controls, at the doses of 50 mg/kg (grooming: q = 7.227 at p<0.001; rearing: q = 4.018 at p<0.001) and 100 mg/kg (grooming: q = 8.221 at p<0.001; rearing: ns), respectively. For both parameters, the maximum effect seems to be already reached with the smaller dose. As a matter of fact, the response was even lower with the higher dose of 100 mg/kg. Although diazepam (1 mg/kg) did not alter the number of crossings, it significantly decreased both grooming and rearing (60% and 69% decreases, respectively), as compared to controls. The flumazenil pretreatment increased diazepam effects on the number of crossings as well as the rearing behavior, by 117 (q = 16.165 at p<0.01) and 105% (q = 11.254 at p<0.001), respectively. However, the pretreatment with flumazenil did not significantly change PIP effects, except for those on grooming behavior whose values were brought close to control ones.

In the rota rod test (Table 3), PIP did not produce any motor incoordination or muscle relaxation, as demonstrated by the number of falls and time of permanence on the bar, the two parameters measured in this test, as compared to controls. Neither of these effects were detected with diazepam alone or with the combination of PIP or diazepam plus flumazenil.

In the forced swimming test (Table 4), significant and dose-dependent decreases of 41% and 75% in the immobility time were observed, after administration of PIP at the doses of 50 (q = 6.997 at p<0.001) and 100 mg/kg (q = 12.496 at p<0.001), respectively, as compared to controls. These results are indicative of an antidepressant effect of PIP. Similarly, imipramine, a classical antidepressant drug used as positive standard, also decreased this parameter by 67% (q = 11.214 at p<0.001).

Although, in the PTZ-induced seizures test (Table 5), PIP did not alter the latency time for the onset of the first convulsion, as compared to controls, it significantly reduced the latency time to death. Thus, PIP at the doses of 50 and 100 mg/kg decreased in 58 (q = 6.017 at p<0.001) and 60% (q = 5.981 at p<0.001) the latency time to death, as compared to controls. On the other hand, as expected, diazepam significantly increased both parameters, the latency time to the first convulsion (around a 19-time increase: q = 32.630 at p<0.001) and the latency time to death (around a 1.8-time increase: q = 8.004 at p<0.001). This is surprising, since PIP showed an anxiolytic effect in the elevated plus maze test.

Discussion

In the present work, we showed a potent anxiolytic activity in piplartine, a bioactive compound isolated from Piper tuberculatum, as assessed by the open field and elevated plus maze tests. The effect of piplartine was comparable to that of diazepam, an anti-anxiety agent. Although piplartine did not alter the number of crossings, indicative of a sedative effect, it significantly increased grooming and rearing behaviors. The open field test is utilized to evaluate the animal emotional state. Thus, animals removed from their acclimatized cage and placed in a novel environment express anxiety and fear, by showing alteration in all or some parameters, such as decreases in ambulation and exploration, immobilization or "freezing", reduction in normal rearing and in grooming behavior, and increased micturition and defecation due to augmented autonomic activity (Novas et al., 1988; Bhattacharya et al., 1991; Bhattacharya, 1994). These paradigms are attenuated by classical anxiolytics, and potentiated by anxiogenic agents. Likewise, the elevated plus maze test is based on the principle that exposure to an elevated and open arm maze leads to an approach conflict that is considerably stronger than that evoked by exposure to an enclosed maze arm. Thus, the total of entries and the time spent in the open arms provide a measure of anxiety or fear-induced inhibition of the normal exploratory activity.

Although the literature is plenty of data on biological activities of the kava extract and its constituents, isolated from another species of Piper, Piper methysticum, almost no studies are found on Piper tuberculatum. Thus, kava lactones also referred as kava-pyrones are the most important active constituents in kava extracts, and thought to have antianxiety, analgesic, muscle relaxing and anticonvulsant effects. However, most of the studies that deal with the evaluation of anxiolytic properties of kava extracts are pre-clinical (Rex et al., 2002; Garrett et al., 2003; Singh and Devkota, 2003) or clinical works (Malsch and Kieser, 2001; Bilia et al., 2002; Pittler and Ernst, 2003; Singh and Singh, 2002; Cagnacci et al., 2003; Thompson et al., 2004; Witte et al., 2005; Lehrl, 2004; Connor and Davidson, 2002).

In the present study, we observed that piplartine, an alkaloid-type amide isolated from P. tuberculatum, significantly increased the number of entrances in the open arms as well as the time of permanence in the open arms, suggesting an anxiolytic effect similar to that of diazepam. However, no effect was observed in the rota rod test, used for evaluation of the animal's motor coordination. Then, our results indicate that piplartine has no sedative effect, at the range of doses used.

The forced swimming test is the most widely used tool for assessing antidepressant activity pre-clinically (Cryan et al., 2002). The widespread use of this simple model is mainly due to its ability to detect a broad spectrum of antidepressant agents (Lister, 1987). The test is based on the observation that rodents (rats and mice), following initial escape-oriented movements, develop an immobile posture when placed inside an inescapable cylinder with water. The immobility is thought to reflect either a failure of persistence in escape-directed behavior (i.e., despair behavior) or the development of a passive behavior, meaning the loss of the animal's ability to cope with stressful stimuli (Archer, 1973). In the present study, we showed that piplartine in a way comparable to imipramine, a tricyclic antidepressant drug, significantly decreased the immobility time, indicative of an antidepressive effect. At the dose used (100 mg/kg), piplartine was as potent as imipramine.

Behavioral and biochemical data indicate the involvement of the dopamine neurotransmitter system in the pathophysiology of anxiety and depression (Rogoz et al., 2002). It is well established that stress activates the mesocorticolimbic DA system, and increases extra-cellular DA in the nucleus accumbens septi and medial prefrontal cortex, inducing anxiolytic-like behavioral effects (Cabib and Puglissi-Allerga, 1994; Dunn, 1988; Salamone, 1994). There is also evidence that stress-induced increases in DA metabolism can be attenuated by antianxiety drugs, such as diazepam (Decker and Mcgaugh, 1991; Cunha et al., 2000).

Animal studies (Costall et al., 1987; Pich and Samanin, 1986) showed that D2 receptor antagonists such as haloperidol present anxiolytic-like effects. Furthermore, D2 agonists have been suggested to be involved in anxiety, because low doses of apomorphine or quinpirole, for instance, reduced anxiety, whereas higher doses produced anxiogenic-like effects (Gao and Cutler, 1993; Simon et al., 1993). However, biochemical studies indicated that haloperidol and quinpirole show affinity not only for D2 but also for D3 receptors (Sokoloff et al., 1990), It has been demonstrated that mice without functional D3 receptors show a reduced anxiety in the open field and elevated plus maze tests (Steiner et al., 1998). Furthermore, putative D3 receptor antagonists were reported to evoke rodent behaviors which may be considered as an anxiolytic action of these compounds (Rogoz et al., 2000). Recent data (Rogoz et al., 2004) suggest that preferential receptor agonists may play a role in the therapy of anxiety and/or depression. In addition, repeated administration of antidepressants, including imipramine, significantly increased D3 receptor mRNA expression, in the nucleus accumbens, and enhanced the activity of central mesolimbic D2 and D3 receptors (D'Aquila et al., 2000; Maj et al., 1998; Ventulani and Nalepa, 2000).

Surprisingly, in the present study, we observed that piplartine in the model of PTZ-induced convulsion did not alter the latency to the first convulsion, and significantly decreased the latency to death, unlikely diazepam that, as expected, significantly increased both parameters.

At the neuronal level, seizure activity often occurs when glutamatergic excitatory neurotransmitters overrides GABA-mediated inhibition. PTZ-evoked seizures can be either of the limbic type or generalized tonic-clonic seizures, dependeng on the PTZ dose used (Del-Bel et al., 1997). Limbic seizures are generally evoked by activation of forebrain excitatory mechanisms (Lemos and Cavalheiro, 1995), while PTZ tonic-clonic seizures are related to GABAergic neurotransmission dysfunction (Del-Bel et al., 1997). PTZ-induced seizures are similar to the symptoms observed in petite mal epilepsy (absence seizures), and drugs useful in the treatment of this type of epilepsy suppress PTZ-induced seizures (Marescaux et al., 1984). Earlier studies (Kasture et al., 2000) have shown that the blockade of post-synaptic 5-HT receptors and inhibition of serotonergic transmission inhibited lithium-pilocarpine-induced seizures, and also suppressed PTZ-induced seizures.

Furthermore, several antidepressants are known to lower the seizure threshold in susceptible patients (Rosenstein et al., 1993; Trimble et al., 1977; Trimble, 1978), and buspirone was also reported to be proconvulsive in mice (Vohora and Pillai, 1998). It has been suggested that the epileptogenic effects of tricyclic antidepressants are a consequence of enhanced monoaminergic transmission. Recently, Khanam et al. (2001), showed that buspirone produced a potent reduction in swimming induced immobility, when combined with doses of IMI or FLU, and failed to affect immobility in mice, in the forced-swimming test. The authors suggest that the tricyclic antidepressant effect in the presence of buspirone is probably mediated through 5-HT1A autoreceptors (Przegalinski et al., 1990). Furthermore, venlafaxine, an atypical antidepressant drug, was shown to be also involved with seizures when the drug is used at high doses or combined with other medications (Santos et al., 2002). Thus, rats receiving doses of 75 mg/kg or higher ones presented increased severity of convulsion in the PTZ-induced convulsion model. As a matter of fact, venlafaxine-treated animals showed a reduction in death latency, and also a tendency towards an increase in the latency time to the first convulsion. These findings suggest that venlafaxine, at doses of 25 and 50 mg/kg, presents a tendency to an anticonvulsant effect, whereas doses of 75-150 mg/kg presented clear pro-convulsant effects in rats, in the PTZ-induced convulsions model.

In the present paper, PIP showed a profile similar to that observed with buspirone and even venlafaxine, presenting no sedation and an anxiolytic effect that was blocked by flumazenil. This finding suggests that PIP might interact with benzodiazepine receptors. In addition, PIP in the PTZ-induced convulsion model decreased the latency to death, as well as the latency to the first convulsion, indicating a decreased threshold to seizures. Possibly, PIP is acting on the monoaminergic neurotransmission system, since the drug, similarly to IMI, also showed a potent antidepressant effect, as assessed by the forced swimming test. Besides, it also presented a pro-convulsive effect in the PTZ-induced convulsion. A similar effect was previously observed with buspirone, a widely used anxiolytic drug (Vohora et al., 1998) which has been shown to potentiate PTZ-induced convulsions in mice and to reverse the anticonvulsant effect of diazepam. Altogether, our results point out to the potential use of PIP as an anxiolytic and antidepressant drug. However, the possible pro-convulsant effect of PIP deserves further attention.

Acknowledgments

The authors are grateful to the Brazilian National Research Council (CNPQ) for the financial support and to Professor M.O.L. Viana for the orthographic revision of the manuscript.

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F. Cicero Bezerra Felipe*, Jucelio Trajano Sousa Filho, Louise Emanuele de Oliveira Souza, Jefferson Alexandre Silveira, Daniel Esdras de Andrade Uchoa, Edilberto Rocha Silveira, Otilia Deusdenia Loiola Pessoa, Glauce S. de Barros Viana

Department of Biophysiology, Faculty of Medicine of Juazeiro do Norte (FMJ), Department of Organic Chemistry of the Federal University of Ceara (UFC), Brazil

*Corresponding author.

E-mail address: Osorio@roadnet.com.br (F. Cicero Bezerra Felipe).
Table 1. Effects of piplartine (PIP) from Piper tuberculatum on the
elevated plus maze test in mice

Groups TPOA NEOA

Control 51.60[+ or -]4.85 (20) 3.80[+ or -]0.36 (20)
Diazepam 219.17[+ or -]9.88 (a) (17) 9.64[+ or -]1.26 (a) (17)
Diazepam + FLU 101.09[+ or -]6.99 (a,b) 9.20[+ or -]0.41 (a) (10)
 (11)
PIP 50 (mg/kg) 105.07[+ or -]12.63 (a) (13) 7.61[+ or -]0.52 (a) (13)
PIP 100 (mg/kg) 154.26[+ or -]9.97 (a) (15) 6.26[+ or -]0.53 (a) (15)
PIP 100 + FLU 65.11[+ or -]8.82 (e) (09) 4.44[+ or -]0.64 (09)

Results are expressed as mean[+ or -]SEM of the number of mice in
parenthesis, a and b as compared to controls and diazepam, respectively,
at p<0.05 (ANOVA and Student-Newman-Keuls as the post-hoc test). Time of
permanence in the open arms (TPOA, in seconds) and number of entries in
the open arms (NEOA) were the parameters studied.

Table 2. Effects of piplartine (PIP) from Piper tuberculatum in the open
field test in mice

Groups NC NG

Control 47.81[+ or -]4.07 (16) 3.17[+ or -]0.58 (17)
Diazepam 42.31[+ or -]4.70 (16) 1.29[+ or -]0.18 (a) (17)
Diazepam + FLU 104.09[+ or -]5.68 (a,b) 3.45[+ or -]0.39 (b) (11)
 (11)
PIP 50 (mg/kg) 53.00[+ or -]2.95 (13) 6.46[+ or -]0.61 (a) (13)
PIP 100 (mg/kg) 53.30[+ or -]4.20 (13) 7.00[+ or -]0.53 (a) (12)
PIP 100 + FLU 58.44[+ or -]3.91 (09) 2.37[+ or -]0.37 (e) (08)

Groups NR

Control 16.93[+ or -]3.87 (16)
Diazepam 5.29[+ or -]1.88 (a) (17)
Diazepam + FLU 34.72[+ or -]1.84 (a,b) (11)
PIP 50 (mg/kg) 27.07[+ or -]1.81 (a) (13)
PIP 100 (mg/kg) 20.83[+ or -]1.79 (a) (12)
PIP 100 + FLU 25.77[+ or -]3.15 (a) (09)

Results are expressed as mean[+ or -]SEM of the number of mice in
parenthesis. a and b as compared to controls and diazepam, respectively,
at p<0.05 (ANOVA and Student-Newman-Keuls as the post hoc test). Number
of crossings (NC), number of groomings (NG) and number of rearings (NR)
were the parameters studied.

Table 3. Effects of piplartine (PIP) from Piper tuberculatum in the rota
rod test in mice

Group NF TP (s)

Control 0.00 (20) 60 (20)
Diazepam 0.00 (15) 60 (15)
Diazepam + FLU 0.00 (11) 60 (11)
PIP 50 0.00 (12) 60 (12)
PIP 100 0.00 (15) 60 (15)
PIP 100 + FLU 0.00 (09) 60 (09)

Results are expressed as mean[+ or -]SEM of the number of mice in
parentheses (ANOVA and Student-Newman-Keuls as the post hoc test).
Number of falls (NF) and time of permanence (TP) were the parameters
studied.

Table 4. Effects of piplartine (PIP) from Piper tuberculatum in the
pentylenetetrazole PTZ-induced seizures test in mice

Group Latency (s) Death (s)

Control/PTZ 89.16[+ or -]8.57 (18) 1000.33[+ or -]154.12 (18)
Diazepam/PTZ 1688.57[+ or -]11.43 (a) 1800.00[+ or -]0.00 (a) (14)
 (14)
PIP 50/PTZ 85.31[+ or -]7.80 (16) 420.68[+ or -]51.25 (a) (16)
PIP 100/PTZ 77.05[+ or -]6.49 (17) 402.78[+ or -]81.85 (a) (14)

Results are expressed as mean[+ or -]SEM of the number of mice in
parentheses. Animals were injected with PTZ only (controls) or
previously treated with diazepam or piplartine. a, as compared to
controls at p<0.05 (ANOVA and Student-Newman-Keuls as the post hoc
test). The latency for the first convulsion and the time of death after
the first convulsion were the parameters studied.

Table 5. Effects of piplartine (PIP) from Piper tuberculatum in the
forced swimming test in mice

Group Time of immobility (s)

Control 96.94[+ or -]6.40 (19)
Imipramine 31.58[+ or -]4.32 (a) (17)
PIP 50 57.31[+ or -]7.58 (a) (19)
PIP 100 24.11[+ or -]3.16 (a) (17)

Results are expressed as mean[+ or -]SEM of the number of mice in
parentheses. a as compared to controls, at p<0.05 (ANOVA and Student-
Newman-Keuls as the post hoc test). The time of immobility was the
parameter studied.
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Author:Felipe, F. Cicero Bezerra; Filho, Jucelio Trajano Sousa; de Oliveira Souza, Louise Emanuele; Silveir
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:3BRAZ
Date:Sep 1, 2007
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