ORIGINAL ARTICLE
CRAVEIRO, Raquel Magalhães Castelo Branco [1], NONATO, Dayanne Terra Tenório [2], ANDRADE, Isadora Porto de [3], NOGUEIRA, Antônio Adriano da Rocha [4], CUNHA, Arcelina Pacheco [5], RICARDO, Nágila Maria Pontes Silva [6], ASSREUY, Ana Maria Sampaio [7], CHAVES, Edna Maria Camelo [8]
CRAVEIRO, Raquel Magalhães Castelo Branco et al. Protective effect of Caesalpinia Ferrea galactomannan in a mice model of seizures. Revista Científica Multidisciplinar Núcleo do Conhecimento. Year. 10, Ed. 09, Vol. 01, pp. 05-23. September 2025. ISSN: 2448-0959, Link de acesso: https://www.nucleodoconhecimento.com.br/biology/caesalpinia-ferrea, DOI: 10.32749/nucleodoconhecimento.com.br/biology/caesalpinia-ferrea
Epilepsy is a public health problem of social and economic impact, characterized by the brain predisposition to generate persistent seizures accompanied by an increased oxidative stress. Plant polysaccharides emerge as an alternative therapy due to its immunomodulator and neuroprotective effects, along with low toxicity. The aim of this study was to evaluate the neuroprotective and antioxidative effects of the galactomannan isolated from the endosperm of C. ferrea (Cf-GM) in the mice model of pentylenetetrazole-induced seizures. Male Swiss mice (25-35 g) were treated by intraperitoneal (I.p.) route with Cf-GM (1-27 mg/kg) or 0.9% NaCl. Thirty min later, the animals were submitted to behavioral tests (open field, elevated plus maze, hole board, tail suspension and acute seizures). The anticonvulsant effect was evaluated in the model of acute seizures induced by pentylenetetrazole- PTZ (70 mg/kg; (I.p.) and the oxidative stress quantified in brain areas (prefrontal cortex, hippocampus and corpus striatum). Cf-GM inhibited the exploratory behavior, reducing the number of crossing (29-54%) and rearing (61-78%) in the Open Field test. Cf-GM also inhibited the permanence time and the entrance number in the open arms of the elevated plus maze, and the number of head dips (46-73%) in the hole board but increased (49%) the immobility time in the tail suspension test. In the model of seizures, Cf-GM increased the death latency and the animal’s survival, inhibiting the oxidative stress via reduction of malondialdehyde (MDA) and increase of reduced glutathione (GSH). The galactomannan of C. ferrea exhibits protective effects, modulating biomarkers of oxidative stress in the mice model of pentylenetetrazole-induced seizures.
Keywords: Brain, Oxidative stress, Convulsion, Plant polysaccharide, Behavior.
Epilepsy is a public health problem of social and economic impact that affects about 50 million people worldwide, being the second most common neurological disorder after stroke (Fiest et al., 2017; Milligan, 2021) It is characterized by the brain predisposition to generate persistent seizures, accompanied by an increased oxidative stress (Fiest et al., 2017). The pharmacological therapy of epilepsy causes several adverse effects, such as vertigo, amnesia and leukopenia, being 30% of patients refractory to treatment (Sankaraneni & Lachhwani, 2015; Shorvon et al., 2018).
The animal model of pentylenetetrazole-induced seizures is widely used in preclinical screening of new anticonvulsant drugs, since pentylenetetrazole (PTZ) administered by intraperitoneal or intravenous route increases neuronal excitability via competitive blockade of GABAA receptors. In the PTZ-induced seizures there is also an increased oxidative stress in the cerebral cortex, mainly in hippocampus accompanied by increased levels of malondialdehyde (MDA) and reduced activity of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (Akula, Dhir & Kulkarni, 2009). Thus, the blockade of PTZ-induced seizures in rodents could be indicative of a depressor effect in the central nervous system by anticonvulsant drugs.
Plant polysaccharides are polymeric carbohydrates that emerge as alternative therapy due to its immunomodulator properties, low toxicity and antioxidant (Zheng et al., 2020). In the Central Nervous System (CNS) they elicit pharmacological effects such as neuroprotective (Chen, Chen & Qin, 2011), anti-inflammatory, antioxidant (Chen et al., 2014), anticonvulsant (Nonato et al., 2018; Nonato et al., 2024) and antidepressant (Wang et al., 2010). Caesalpinia ferrea or Libidibia ferrea (Leguminosae family) is a native species of Brazil, popularly known as jucá (Queiroz, 2009). Studies have demonstrated that the crude aqueous extract of C. ferrea leaves presents antioxidant effect mediated by the reduction of MDA in the mice model of arthritis induced by zymosan (Falcão et al., 2019). Besides, C. ferrea polysaccharides isolated from pods and barks present anti-inflammatory effect in the acute inflammation models of paw edema and peritonitis (Pereira et al., 2012), and healing effect in the model of excision skin wounds in normo- and hyperglycaemic rats (Pereira et al., 2016; Assreuy et al., 2023). In respect to galactomannans they are hydrophilic polysaccharides mostly present in the endosperm of leguminous, containing in its structure mannose, galactose, rhamnose and glucose (Bento et al., 2013). The galactomannan isolated from C. ferrea (Cf-GM) seeds possesses 2.4:1 ratio mannose/galactose, revealed by 1H NMR or 2.7:1 by 13C NMR, composed by 33.58% of mannose and 12.39% of galactose, and low content of arabinose (0.06%) and glucose (0.94%) (Cunha et al., 2016). The same study demonstrated that the C. ferrea galactomann presents in vivo antidiabetic effect, being devoid of significant toxicity (Cunha et al., 2016). The objective of this study was to evaluate the neuroprotective effects through behavioral tests and oxidative stress of C. ferrea galactomannan in the mice model of seizures induced by pentylenetetrazole.
C. ferrea pods were collected at Pici Campus of Federal University of Ceará (FUC) and a voucher specimen (44695) was deposited at the Herbarium Prisco Bezerra/FUC. Seeds were removed from pods and immersed in distilled water during 30 min at 85 °C for endosperm removal, that was placed in a solution of water:alcohol (1:4, v/v) at 60 °C for 20 min in order to exclude phenolic pigments. The depigmented endosperm (10 g) was lyophilized, solubilized (900 ml distilled water), maintained at 75 °C for 4 h, filtered and precipitated with a solution of 97% ethanol (1:3, v/v) for 4 h, followed by three precipitation cycles with a solution of 99% ethanol (1:1, v/v), filtration and centrifugation (Cunha et al., 2016). The gelatinous pellet containing the galactomannan of C. ferrea was named Cf-GM.
Male Swiss mice (25 – 35 g, two months old) were provided by the Central Animal House from Federal University of Ceará-Brazil, maintained in controlled environment (22 ± 2 °C, 12/12 h light-dark cycle), with free access to food and water, and allowed to adapt to the laboratory for at least 1 h before experiments.
The experimental protocols were performed during the light phase of the cycle, in accordance with the Guide for the Care and Use of Laboratory Animals by the National Academy of Sciences, The National Academies Press, Washington, D.C. and Brazilian College of Animal Experimentation (COBEA), approved by the Ethics Committee for Animal Use (UECE N° 3484042/2017) and NC3R´s ARRIVE guidelines.
The animals (N=88) were divided into 7 experimental groups (n=7-10), receiving the following treatment by intraperitoneal (I.p.) route: Group 1 (Cf-GM 1 mg/kg); Group 2 (Cf-GM 9 mg/kg); Group 3 (Cf-GM 27 mg/kg); Group 4 (0.9% NaCl – sterile saline); Group 5 (Diazepam 1 mg/kg); Group 6 (Diazepam 2 mg/kg); Group 7 (Imipramine 10 mg/kg).
Thirty minutes after treatment the animals were evaluated by the tests (open field, elevated plus maze, hole board, tail suspension, acute seizure). Diazepam or imipramine provided from St. Louis, MO, USA were used as standard drugs. Diazepam at 1 mg/kg was administered for the anxiolytic and anticonvulsant effects in the elevated plus maze, hole board, and at 2 mg/kg for the sedative effect in the open field test.
The exploratory activity (n° crossings, rearing and grooming) was observed over 4 min after 1 min adaptation by the mice placement in the open field apparatus, an acrylic box (30 x 30 x 15 cm) divided into 9 squares (Archer, 1973).
For evaluation of the anxiety behavior in the elevated plus maze, mice were placed in the center of the plus maze apparatus, which consists of two opposing open and closed arms (30 x 5 x 25 cm), with the head turned towards one of the closed arms. The frequency of entry and the time spent in each arms were observed during 5 min (Lister, 1987). The evaluation of the anxiety behavior in the hole board test, mice were placed in the hole board apparatus (20 x 20 cm), containing 16 equidistant holes, for recording the number of entrances in the holes during 5 min (Lister, 1987).
The depressive behavior (immobility time) of mice, suspended 50 cm from the ground by a fixed tape 1 cm from the tail tip, was observed during 5 min (Steru et al., 1985).
Thirty minutes after treatment, the acute seizures were induced by the administration of pentylenetetrazole (PTZ; 70 mg/kg, I.p.). For this, the animals were placed in individual cages during 20 min for evaluation of the onset time of first clonic or tonic-clonic seizure (seizure latency) and first clonic or tonic-clonic seizure to death (death latency), and also the percentage of survival (Czuczwar & Frey, 1986). After being tested the animals were euthanized by beheading, and the brain was dissected for evaluation of oxidative stress markers in pre-frontal cortex (PFC), hippocampus (HC) and striatum (ST).
The homogenates of brain tissues (PFC, HC, ST) were prepared in phosphate buffer sodium (pH 7.4) according to the weight of the tissues. They were stored in 80° C frezzer for further quantification of MDA by the method of TBARS at A535 nm (Yagi, 1976) and reduced glutathione (GSH) by DTNB method at A412 nm (Sedlak & Lindsay, 1968).
Results were expressed as mean ± standard error of the mean (S.E.M.) and analyzed by One-way ANOVA, followed by Tukey´s and Dunnet´s (elevated plus maze test) post hoc tests. The significance level was set at p <0.05.
Cf-GM reduced the number of crossings by at 59% in the dose of 9 mg/kg (group 2) (30.57 ± 2.15; p < 0.0001) and 54% at 27 mg/kg (group 3) (34.17 ± 6.33; p = 0.0003), compared to saline (group 4) (70.00 ± 7.12), with f value (f [4.29] = 14.70). In addition, there was a reduction by 63% in the number of crossings between animals treated with Cf-GM at 1 (group 1) (53.29 ± 5.66) and 9 mg/kg (Figure 1A). Cf-GM reduced by 71% the number of rearing at 1 mg/kg (8.28 ± 1.96; p< 0.0001), 61% at 9 mg/kg (11.29 ± 1.52; p = 0.0012) and by 78% at 27 mg/kg (6.42 ± 2.34; p< 0.0001), compared to saline (28.57 ± 2.89) (f [4.42] = 18.96) (Figure 1B). However, the number of grooming was unaltered at any dose (Figure 1C). The sedative drug diazepam (2 mg/kg) (group 6) reduced both the number of crossing (22.86 ± 1.95) and rearing (4.33 ± 0.77), compared to saline, but did not alter the number grooming.
Figure 1- Cf-GM reduces the number of crossing and rearing in the open field test
In the open arms, Cf-GM reduced the permanence time at all doses: 1 (39.43 ± 6.12 s; p = 0.0316) corresponding to 56% ,9 (36.33 ± 5.67 s; p = 0.0284) with a reduction of 60 % and 27 mg/kg (27.83 ± 9.91 s; p = 0.0095) reducing the time in 69% versus saline (90.25 ± 16.98 s), with F value (F [4.29] = 5.685). CF-GM also reduced the entrance number at the dose of 27 mg/kg (2 ± 0.63; p = 0.0217) by 72% versus saline (7.16 ± 0.98) with F value (F [4.30] = 7.421) (Figure 2A/B).
However, in the closed arms, Cf-GM increased both the permanence time by 36% (1 mg/kg: 231.9 ± 7.82 s; p= 0.0033) and 46% (9 mg/kg: 249.3 ± 12.02 s; p = 0.0003) versus saline (170.9 ± 13.27 s) with F value (F [4.29] = 64.57), and the entrance number by 56% only at 9 mg/kg (12.29 ±1.20; p = 0.0288), compared to saline (7.87 ± 1.17) (F [4.29] = 12.67) (Figure 2C/D). The anxiolytic drug diazepam at 1 mg/kg (group 5) reduced the permanence time (2.85 ± 0.63 s; p = 0.0006) and the entrance number (0.83 ± 0.30; p < 0.0001) in the closed arms but did not alter these behaviors in the open arms.
Cf-GM at all doses reduced the number of head dips: 1 mg/kg (20.00 ± 2.04; p = 0.0094) reduced by 46%, 9 mg/kg (18.00 ± 1.69; p = 0.0032) reduced by 51% and 27 mg/kg (9.85 ± 1.61; p < 0.0001) with 73 % compared to saline (37.00 ± 4.34), with F value (F [4.27] = 21.41) (Figure 2E). The anxiolytic drug diazepam at 1 mg/kg did not alter this behavior.
Figure 2- Inhibitory effect of Cf-GM in the elevated plus maze and hole board tests
Cf-GM increases immobility time in the tail suspension test Cf-GM (9 mg/kg) increased by 49% (F [4.26 = 5.868]) the immobility time (117.2 ± 10.06 s vs. saline: 59.71 ± 8.50 s) with p = 0.0163, while the tricyclic antidepressant imipramine at 10 mg/kg (group 7) did not alter this behavior (Figure 3).
Figure – 3 Cf-GM increases immobility time in the tail suspension test
Cf-GM caused no effect on seizure latency but increased the death latency at 27 mg/kg (F [4.43] = 7.884; p= 0.0126), and animals survival at 9 and 27 mg/kg compared to saline. The anticonvulsant drug diazepam at 1 mg/kg showed protective effect on the seizure and death latencies (Table 1).
Table 1-Cf-GM increases death latency in the model of seizures induced by pentylenetetrazole
| Treatment (mg/kg) | Seizures latency (s) | Convulsed animals (%) | Death latency (s) | Survival (%) |
| Saline | 53.5 ± 3.79 | 100 | 229.3 ± 45.39 | 00 |
| Cf-GM (1) | 74.7 ± 4.79 | 100 | 374.6 ± 116.9 | 00 |
| Cf-GM (9) | 84.2 ± 6.03 | 100 | 494.9 ± 98.74 | 10 |
| Cf-GM (27) | 82.4 ± 14.3 | 100 | 786.3 ± 129.1* | 50 |
| Diazepam (1) | 121.1 ± 12.7 * | 100 | 1046 ± 101.4* | 60 |
Note: *p<0.05 vs. Saline (n=10). 1 Cf-GM: C. ferrea galactomannan. One-way ANOVA followed by Tukey´s post-hoc test.
Source: Researcher’s result 2024.
MDA was reduced by Cf-GM in PFC at this doses: 1 mg/kg (72% – 230.8 ± 22.42; p < 0.0001), 27 mg/kg (58% – 351.5 ± 20.22; p< 0.0001) vs. PTZ: 832.9 ± 104.3 nmol/mg, with F value (F [2.20]= 35.07), HC: 1 mg/kg (51% – 336.1 ± 34.82; p< 0.0001), 27 mg/kg (44% – 385.7 ± 27.57; p = 0.0002) vs. PTZ: 685.4 ± 54.48 nmol/mg (F [2.21]= 21.42), and ST : 1 mg/kg (41% – 332.9 ± 29.27 vs. PTZ: 562.8 ± 59.84 nmol/mg) with p = 0.009 and F value (F [2.24]= 7.034) (Figure 4A/C). On the other hand, GSH was increased at the same doses by Cf-GM in PFC: 1 mg/kg (48% – 1456 ± 182.3; p= 0.0256), 27 mg/kg (53% – 1636 ± 313.2; p= 0.0067) vs. PTZ: 756.7 ± 73 71 µmol/ml (F [2.23]= 7.019), HC: 1 mg/kg (52% – 1733 ± 220.1; p= 0.0191), 27 mg/kg (50% – 1641 ± 327.5; p= 0.0364) vs. PTZ: 826.2 ± 99.98 µmol/ml (F [2.20]= 5.632), and ST: 1 mg/kg (48% – 1658 ± 264.00; p = 0.0134), 27 mg/kg (55% – 1909 ± 202.3; p=0.0019) versus PTZ: 863.0 ± 91.01 µmol/ml (F [2.22]= 9.033) (Figure 4D/F).
Figure 4- Cf-GM reduces the brain content of MDA and increases that of GSH in pentylenetetrazole-induced seizures
Cf-GM reduced MDA in PFC: 1 mg/kg (79% – 78.39 ± 4.96), 9 mg/kg (81% -74.41 ± 1.57) vs. saline: 368.80 ± 26.47 nmol/mg (F [2.19]= 126.8 ), HC: 1 mg/kg (80%- 81.46 ± 4.49), 9 mg/kg (80% – 77.53 ± 3.55) vs. saline: 399.2 ± 64.12 nmol/mg (F [2.18]= 24.71) , and ST: 1 mg/kg (80% – 73.55 ± 2.89), 9 mg/kg (81% – 69.74 ± 2.06) vs. saline: 375.7 ± 45.20 nmol/mg (F [2.20]= 41.98) , all with p value < 0.0001 (Figure 5A/C). However, GSH was not altered at any brain area (Figure 5D/F).
Figure 5- Cf-GM per se reduces the brain content of MDA
This study demonstrated central inhibitory behavior of Cf-GM in the open field, elevated plus maze, hole board and tail suspension tests, and in the model of pentylenetetrazole-induced seizures, modulating biomarkers of oxidative stress. The central inhibitory effect was seen in the open field test by the reduction in the number of crossings and rearing. These data are in accordance with those demonstrated in the tail suspension test, useful to the screening of antidepressant drugs (Can et al., 2019), in which Cf-GM (9 mg/kg) increased the animal’s immobility time, suggesting depressive behavior. However, Cf-GM did not alter the grooming in the open field. This data seems to be contradictory, although it is accepted in the literature that this behavior is altered only in presence of a stressor stimuli, at least in rats (Van Erp et al., 1994). In this study, it was also demonstrated that Cf-GM presents stimulant-like effect either in the elevated plus maze (reduction of permanence time and number of open rms entries) as in the hole board (reduction in the number of head dips), specific tests to evaluate anxiety behavior. In fact, the inhibitory behavior in exploratory activity indicates indirect effect on anxiety (Prut & Belzung, 2003), reinforcing the anxiogenic effect of CF-GM. These data are in accordance to other behavioral studies using plant polysaccharides (Nonato et al., 2018; Manoj & Sasmal, 2014; Yang et al., 2013). In the model of PTZ-induced seizures, Cf-GM (27 mg/kg) was protective, increasing the latencies of death and animal’s survival. In line with these, the aqueous extracts of Albizia glaberrima (Adebisi, Akindele & Adeyemi, 2015) and Ebenus stellate (Khodaparast, Sayyah & Sardari, 2011) presented anticonvulsant effect in this model. However, Cf-GM caused no significant effect on seizure latency. It is well known that free radical production is associated with damage to cellular structures in pathological conditions of the central nervous system, such as Parkinson’s disease, stroke, dementia and epilepsy (Adibhatla & Hatcher, 2008). In this context, the literature has reported protective effects of plant polysaccharide extracts in several experimental models: a) reperfusion ischemia – Euphoria longa fruits (Can et al., 2019), Ginkgo biloba leaves (Yang et al., 2013), Angelica sinensis roots (Ai et al., 2013); b) strychnine- and PTZ-induced seizures – Genipa americana leaves (Nonato et al., 2018); c) cognitive impairment induced by D-galactose – Millettia pulchra (Lin et al., 2014). Accordingly, in the model of PTZ-induced seizures Cf-GM reduced MDA content and increased GSH in all brain areas (CPF, HP, CE). Besides, Cf-GM per se showed protective effect via reduction of the oxidative marker MDA in all brain areas, without alteration of the antioxidant marker GSH. The antioxidant effect had been already demonstrated for chemically sulfated galactomannan of plant origin (Marques et al., 2015).
Cf-GM exhibits protective effects, explained by the inhibitor effect exhibits in behavioral tests, modulating biomarkers of oxidative stress in the mice model of pentylenetetrazole-induced seizures.
Thus, to fulfill the enormous pharmacotherapy lacunae in this field, the main contribution of this study was to suggest the potential application of Cf-GM for patients during seizure crisis. We emphasize that this research, although relevant, has some limitations, since animal models exhibit varied responses based on genetic and environmental factors that may impact the reproducibility of the results. Moreover, further clinical studies are necessary to confirm the findings in animal models.
This work was supported by grants from CNPq, FUNCAP and CAPES. AMS Assreuy is a senior investigator of CNPq (Process No. 308433/2017-3).
The authors declare no conflict of interest.
Conceptualization: E.C., R.C., Data acquisition: R.C.; D. N., L.L.; Datal analysis: E.C., R.C., A.A.; Galactomannan isolation: A.C.; N.R; S.T. and Z.B.; Writing-original draft preparation: R.C., E.C., A.A.; Writing-review and editing: E.C., R.C., A.A., D.N. All authors have approved the final manuscript version.
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[1] Doctorate and Master’s Degree in Physiological Sciences, Postgraduate Degree in Intensive Care and Bachelor’s Degree in Physiotherapy. ORCID: 0000-0002-5739-5109. Currículo Lattes: http://lattes.cnpq.br/7352496874864678.
[2] Doctorate and Master’s Degree in Physiological Sciences, Postgraduate Degree in Orthopedics and Traumatology. ORCID: 0000-0001-9477-1866.
[3] Master’s student in the Postgraduate Program in Physiological Sciences at the State University of Ceará. Bachelor’s degree in Nursing from the State University of Ceará. ORCID: 0000-0001-9995-8953.
[4] PhD and Master’s student in the Postgraduate Program in Physiological Sciences at the State University of Ceará; Nurse. ORCID: 0000-0002-1760-1609.
[5] Post-doctorate (PNPD/CAPES), with an emphasis on Polymer Chemistry and Nanotechnology; PhD in Chemistry from the Federal University of Ceará; Master’s degree in Chemistry from the Federal University of Ceará, with an emphasis on Biopolymers applied to Biomedicine; Bachelor’s degree in Chemistry from the State University of Ceará. ORCID: 0000-0002-3058-8592.
[6] Postdoctoral fellow – University of Manchester, PhD in Polymer Chemistry – University of Manchester, Master’s degree in Inorganic Chemistry from the Federal University of Ceará and Bachelor’s degree in Industrial Chemistry from the Federal University of Ceará. ORCID: 0000-0003-1849-5403.
[7] Post-Doctorate in Molecular Biology from the University of Virginia-USA (2001), PhD (2000) in Pharmacology from the Federal University of Ceará, Bachelor’s Degree in Biological Sciences (1980), Master’s Degree (1997). ORCID: 0000-0002-2323-5385.
[8] Professor at the State University of Ceará. Supervisor in the Postgraduate Program in Clinical Care, Nursing and Health, and in the Postgraduate Program in Physiology. Advisor. PhD in Pharmacology from the Federal University of Ceará (2012). Master’s degree in Clinical Health Care from the State University of Ceará (2006). Professional Master’s degree in Child and Adolescent Health (2003), Bachelor’s degree in Nursing from the State University of Ceará (1988). ORCID: 0000-0001-7752-3924.
Material received: August 6, 2024.
Material approved by peers: January 17, 2025.
Edited material approved by authors: July 17, 2025.
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