Curcumin attenuates neuroinflammation and improves cognitive function in a rat model of febrile convulsions

Abstract

This study aimed to investigate the effects of curcumin on neuroinflammation and cognitive function in a rat model of febrile convulsions (FC). This study was conducted on 10-day-old male Wistar rat pups, randomly assigned to four groups: Control, Curcumin, FC, and FC + Curcumin. FC were induced by placing the rats in a 44 °C water bath until convulsions occurred or for a maximum of 4 min. Curcumin (200 mg/kg/day) was administered intraperitoneally for seven consecutive days before FC induction. Neuroinflammation was assessed by measuring hippocampal and serum TNF-α and IL-1β levels using ELISA. Cognitive function was evaluated using the Morris Water Maze (MWM) test, where escape latency, swimming speed, and distance traveled were recorded, followed by a probe test on Day 5 to assess memory retention. Motor coordination was assessed using the Rotarod test, measuring latency to fall. Curcumin treatment significantly reduced hippocampal TNF-α levels in the FC model (FC group: 145.3 ± 12.1 pg/mL vs. FC + Curcumin group: 98.6 ± 9.4 pg/mL, p = 0.001). In the MWM test, curcumin-treated rats exhibited shorter escape latencies and improved spatial memory performance compared to the FC group (p < 0.05). By Day 4, the curcumin-treated group had a significantly shorter escape latency (FC group: 42.8 ± 5.9 s vs. FC + Curcumin group: 25.3 ± 4.1 s, p = 0.002) and traveled a shorter distance to reach the platform (FC group: 335.4 ± 22.8 cm vs. FC + Curcumin group: 192.6 ± 18.3 cm, p = 0.001). Curcumin administration significantly reduced FC termination time (FC group: 96.7 ± 7.4 s vs. FC + Curcumin group: 62.5 ± 5.9 s, p = 0.001). Curcumin exerts neuroprotective effects in FC by reducing hippocampal neuroinflammation and improving cognitive function. These findings suggest that curcumin could be a promising therapeutic agent in managing febrile seizure-related neuroinflammation and cognitive dysfunction. Further studies are warranted to explore its long-term efficacy and clinical applicability.

Introduction

Febrile convulsion (FC) is the most common type of convulsion in childhood and is among the most prevalent neurological disorders in children¹. FC occurs due to elevated body temperature, affects the central nervous system, and is not caused by infections. While short-term FC episodes typically do not result in brain damage, prolonged and recurrent FCs are known to cause learning disabilities and cognitive dysfunctions². Several studies have demonstrated that prolonged FC leads to hippocampal edema and accelerates memory loss^3–6. Although FC is generally regarded as a “benign” convulsive disorder, approximately 7% of affected children develop epilepsy during adolescence⁷. Moreover, recurrent FCs have been shown to impair spatial memory performance, as evidenced by animal experiments conducted in the Morris water maze².

The pathogenesis of FC involves complex interactions between immune-inflammatory processes, genetic factors, and cytokine pathway activation¹. Pro-inflammatory and anti-inflammatory cytokines play a crucial role in regulating the febrile response during infections¹. Although the exact pathophysiology of FC is not fully understood, increased activity of tumor necrosis factor-alpha (TNF-α), interleukin (IL)−1β, and IL-6 is believed to contribute to FC development⁸.

On the other hand, both in vitro and in vivo studies have shown that curcumin, a natural compound, reduces cytokine levels⁹. Curcumin is a polyphenolic compound derived from turmeric (Curcuma longa), a member of the Zingiberaceae family. As the most active component of turmeric, curcumin constitutes 2–5% of its content. This compound is widely used for food preservation and coloring and has gained significant attention in medical applications due to its potent anti-inflammatory and antioxidant properties^10,11.

Curcumin possesses antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer properties. It has been demonstrated to reduce the levels of TNF-α, IL-6, and IL-1β in various studies^12,13. Additionally, curcumin has been shown to alleviate cisplatin-induced learning and memory impairments¹⁴. Based on this information, it is hypothesized that curcumin could mitigate inflammation by reducing IL-1β and TNF-α levels in FC and enhance learning and memory performance.

In this study, the effects of curcumin, a polyphenolic compound derived from Curcuma longa, on high cognitive functions and pro-inflammatory cytokines in a rat model of FC were evaluated. The ultimate goal of the study was to develop new therapeutic approaches for FC.

Materials and methods

Study design

The rats used in this study were obtained from the Experimental Animals Research Center of Gaziantep University. Ethical approval for the study was obtained from the Gaziantep University Local Ethics Committee for Animal Experiments (2019/32). All methods were performed in accordance with the relevant guidelines and regulations, including the ethical standards outlined in the ARRIVE guidelines for reporting in vivo experiments and the institutional guidelines of the Gaziantep University Local Ethics Committee for Animal Experiments. Pregnant Wistar Albino rats were housed in a controlled environment with a temperature of 21–22 °C and relative humidity of 60%. A 12-hour light/dark cycle was maintained, and the rats had ad libitum access to food and water. Only male rats were used in the experiments to avoid the effects of fluctuating estrogen levels on neuronal excitability.

On postnatal day 10, rats were placed in a 44 °C water bath for a maximum of 4 min until convulsions were observed. Once convulsions occurred, the rats were removed from the bath and monitored until the convulsions ceased. This process was repeated daily at the same time for 7 days. After each experiment, the pups were returned to their mothers.

Following the establishment of the FC model, the Morris Water Maze (MWM) and Rotarod tests were performed. Finally, blood samples were collected under anesthesia (ketamine 75 mg/kg and xylazine 10 mg/kg, intraperitoneally), and the hippocampus tissues were extracted. Levels of IL-1β and TNF-α in hippocampus and serum samples were analyzed using ELISA kits.

Groups

On postnatal day 10, the rats were divided into four groups, with 7 rats in each group. Experiments were conducted daily for 7 days at the same time. The groups were organized as follows:

• Group 1 (Control Group): Rats were kept in a 37 °C water bath for 4 min, and 10% DMSO (80 ml/kg/day) was administered intraperitoneally (ip) prior to the bath.

• Group 2: Rats were kept in a 37 °C water bath, and 200 mg/kg/day of curcumin was administered ip before the bath.

• Group 3 (FC Group): The FC model was established; 10% DMSO (80 ml/kg/day) was administered ip, and the rats were placed in a 44 °C water bath for a maximum of 4 min.

• Group 4 (FC + Curcumin Group): The FC model was established; 200 mg/kg/day of curcumin was administered ip before the rats were placed in a 44 °C water bath.

No animals were excluded from the study, and all animals successfully completed the experimental protocols.

Febrile convulsion (FC) model

The FC model was established using 10-day-old rats. Each rat was individually placed in a 44 °C water bath and observed until convulsions occurred or a maximum of 4 min elapsed. The time taken until the onset of convulsions was defined as the “FC onset time,” and the time until the convulsions ceased was recorded as the “FC termination time”^15,16.

For the curcumin-treated groups, curcumin (purity ≥ 95%, Cat. No: C1386, Sigma-Aldrich, USA) was dissolved in 10% dimethyl sulfoxide (DMSO) at a concentration of 25 mg/ml. A daily dose of 200 mg/kg was administered intraperitoneally prior to exposure to the 44 °C water bath, following previously established protocols^17,18. This procedure was consistently performed once daily at the same time for seven consecutive days. In control groups that did not receive curcumin treatment, an equivalent volume of DMSO alone was administered intraperitoneally.

Morris water maze test

The Morris Water Maze (MWM) test was used to evaluate learning and memory performance. The MWM test was performed starting on postnatal day 25, after the completion of the febrile convulsion induction and curcumin administration procedures. The test measured escape latency, swimming speed, and distance traveled to locate the hidden platform. MWM is a highly sensitive method for assessing hippocampus-dependent learning¹⁹.

The MWM consisted of a circular tank with a diameter of 180 cm and a depth of 60 cm, filled with water colored using black food dye to obscure the hidden platform. The water temperature was maintained at 22 ± 2 °C. The tank was divided into four quadrants, and the platform, submerged 1–2 cm below the water surface, was placed in the S3 quadrant. The platform’s position remained constant, and visual cues were placed around the tank to aid the rats in learning its location.

The experiment included four days of learning trials followed by a probe test on the fifth day. Daily trials were conducted at 9:00 AM and 3:00 PM. Rats were released from four different starting positions (North, South, East, West) and given 60 s to locate the platform. If they failed, they were guided to the platform and allowed to stay on it for 15 s. Escape latency, swimming speed, and distance traveled were recorded for each trial. During the probe test, the hidden platform was removed, and the time spent in the S3 quadrant was measured. All trials were recorded using a ceiling-mounted camera, and the footage was analyzed using NOLDUS software for metrics such as time spent in S3, swimming speed, and distance traveled.

Rotarod test

The Rotarod test is a method used to evaluate performance, endurance, balance, and coordinated movements²⁰. In this study, although the febrile convulsion induction and curcumin administration protocol started on postnatal day 10 and lasted for 7 days, the Rotarod test was deliberately conducted on postnatal day 29 to allow the animals sufficient developmental maturity for accurate motor function assessment. During testing, rats were placed on a rotating rod set at a constant speed of 30 rpm, and the latency to fall was recorded automatically with second-level precision. Each animal underwent three trials, with a maximum duration of 300 s per trial and a 10-minute interval between consecutive trials²⁰.

Decapitation and hippocampal dissection

Following the completion of the MWM and Rotarod tests, the rats were anesthetized. Blood samples were collected from the vena cava under anesthesia, after which decapitation was performed. The hippocampal tissues were isolated and cleaned of surrounding tissues. Serum and hippocampus samples were stored at −80 °C until the day of the experiment.

Biochemical measurements

Protein isolation from hippocampal tissues was conducted using the BOSTER Antibody and ELISA kit, which included CER A and CER B reagents, according to the manufacturer’s protocol (Qiagen TissueLyserLT, Serial No: 23.1001/07284). Hippocampal homogenates and serum samples were prepared and analyzed for IL-1β levels using the IL-1β ELISA kit (Cat. No: SEA563Ra, Cloud-Clone Corp., Wuhan, China). TNF-α levels were analyzed using the TNF-α ELISA kit (Cat. No: SEA133Ra, Cloud-Clone Corp., Wuhan, China).

Statistical analysis

The data obtained from the experiments were analyzed using IBM SPSS 25.0 software (SPSS Software, Inc., San Diego, USA). The mean and standard deviation (SD) values of the data were evaluated using descriptive statistics after independent experimental repetitions. Normality was assessed using the Shapiro-Wilk test. For non-normally distributed data, the Mann-Whitney U test was used for comparisons between two independent groups, while the Kruskal-Wallis H test and Dunn’s post-hoc test were applied for comparisons among three groups. For normally distributed data, the Student-t test was used for two-group comparisons, and One-Way ANOVA with Tukey’s post-hoc test was applied for three-group comparisons. For repeated measures, Two-Way ANOVA was used when the data followed a normal distribution and variances were equal. A p-value of < 0.05 was considered statistically significant for all group comparisons.

Results

Morris water maze findings

Comparison of speed, distance, and time parameters on day 1 was shown in Table 1. According to the analysis, there was no significant difference in Time 1 (s) and Speed 1 (cm/s) variables among the groups. However, for the Distance 1 (cm) variable, a statistically significant difference was observed between Group 1 and Group 4 (p = 0.01) (Table 1).

Table 1.

Comparison of speed, distance, and time parameters on different days.

Groups	Time (s)	p value (Time)	Distance (cm)	p value (Distance)	Speed (cm/s)	p value (Speed)
On day 1
Group 1	52.55 ± 16.57	p = 0.07	1036.02 ± 423.88	p = 0.01	18.58 ± 5.09	p = 0.33
Group 2	49.71 ± 16.72		1007.15 ± 476.01		18.79 ± 5.71
Group 3	47.68 ± 17.92		850.66 ± 388.17		17.41 ± 3.95
Group 4	42.84 ± 19.39		810.50 ± 468.28		17.55 ± 4.60
On day 2
Group 1	42.70 ± 19.82	p = 0.001	830.54 ± 456.27	p = 0.001	18.17 ± 4.16	p = 0.001
Group 2	27.09 ± 18.40		453.40 ± 430.54		13.96 ± 5.35
Group 3	39.30 ± 21.57		704.24 ± 503.97		15.75 ± 6.07
Group 4	34.77 ± 20.45		645.19 ± 519.96		15.64 ± 5.77
On day 3
Group 1	30.75 ± 19.36	p = 0.01	595.02 ± 470.66	p = 0.001	16.95 ± 4.97	p = 0.001
Group 2	19.16 ± 12.45		278.87 ± 251.49		12.79 ± 4.20
Group 3	36.89 ± 21.08		675.66 ± 474.64		17.12 ± 4.93
Group 4	19.79 ± 12.61		337.89 ± 310.87		14.74 ± 5.82
On day 4
Group 1	21.68 ± 15.71	p = 0.12	339.14 ± 347.70	p = 0.001	14.04 ± 4.78	p = 0.46
Group 2	15.82 ± 12.71		239.75 ± 280.76		12.37 ± 5.90
Group 3	32.12 ± 20.02		474.89 ± 409.67		13.71 ± 5.99
Group 4	19.59 ± 14.49		333.07 ± 368.36		13.63 ± 6.92

ANOVA (F) test was used for statistical comparisons.

Comparison of speed, distance, and time parameters on day 2 was shown in Table 1. The analysis revealed a significant difference between Group 1 and Group 2 in terms of Time 2 (p = 0.001). Similarly, for Distance 2, Group 3 exhibited a significantly higher value compared to Group 2 (p = 0.03). Additionally, a statistically significant difference was found between Group 1 and Group 2 for Speed 2 (p = 0.001) (Table 1).

Comparison of speed, distance, and time parameters on day 3 was shown in Table 1. The analysis revealed that Time 3 in Group 2 was significantly lower compared to Group 1 (p = 0.001). For Distance 3, Group 3 exhibited a significantly greater distance compared to Group 2 (p = 0.001). When evaluating Speed 3, Group 1 demonstrated a significantly higher speed than Group 2 (p = 0.001). Additionally, Group 4 covered a significantly shorter distance than Group 3 (p = 0.001) and found the platform in a significantly shorter time (p = 0.001) (Table 1).

Comparison of speed, distance, and time parameters on day 4 was shown in Table 1. The analysis revealed no statistically significant difference among groups in terms of Time 4 (p = 0.12) and Speed 4 (p = 0.46). However, for the Distance 4 variable, a statistically significant difference was observed between Group 2 and Group 3 (p = 0.001) (Table 1).

Comparison of platform search time are presented in Fig. 1. In Group 1, the platform search time decreased from 52.55 s on Day 1 to 42.7 s on Day 2, 30.75 s on Day 3, and 21.68 s on Day 4. This reduction was statistically significant (Time 1–2, p = 0.01; Time 2–3, p = 0.001; Time 3–4, p = 0.01). In Group 2, the platform search time was 49.71 s on Day 1, 27.09 s on Day 2, 19.16 s on Day 3, and 15.82 s on Day 4. A significant reduction was observed between Time 1–2 (p = 0.001) and Time 2–3 (p = 0.001). In Group 3, the search time decreased from 47.68 s on Day 1 to 39.30 s on Day 2, 36.89 s on Day 3, and 32.12 s on Day 4. However, a statistically significant difference was only found between Time 1–2 (p = 0.00), with no significant change observed in the following days. In Group 4, the search time was 42.84 s on Day 1, 34.77 s on Day 2, 19.79 s on Day 3, and 19.59 s on Day 4. A significant reduction was observed between Time 1–2 (p = 0.02) and Time 2–3 (p = 0.001) (Fig. 1).

Fig. 1.

Platform Search Times of the Groups on Days 1–4 (*p < 0.05; **p < 0.001).

The comparison of Prob Test S3 Duration Prob and S3% Prob Values was shown in Table 2. S3 Duration Prob refers to the time the rats spent in the target quadrant (S3) during the probe trial. S3% Prob represents the percentage of time the rats spent in the same quadrant relative to the total trial duration. An analysis of the table data revealed no statistically significant differences among the groups (p > 0.05) (Table 2).

Table 2.

Comparison of prob test S3 duration prob and S3% prob values.

Group	S3 Time Prob (s)	p value (S3 Time Prob)	S3% Prob (%)	p value (S3% Prob)
Group 1	31.17 ± 10.71	p = 0.96	51.91 ± 17.84	p = 0.96
Group 2	29.19 ± 6.27		48.62 ± 10.44
Group 3	28.77 ± 11.14		47.92 ± 18.56
Group 4	30.53 ± 9.44		50.85 ± 15.73

ANOVA (F) test was used for statistical comparisons.

Rotarod test findings

Descriptive statistical findings of the Rotarod test are presented in Table 3. An analysis of Trial 1 (p = 0.42), Trial 2 (p = 0.13), and Trial 3 (p = 0.34) revealed no statistically significant differences among the groups (p > 0.05) (Table 3.).

Table 3.

Comparison of descriptive statistical findings for the Rotarod test.

	Group	Mean±SD (s)	N	p-value
Trial 1	Group 1	182.00 ± 115.92	7	0.42
	Group 2	199.00 ± 86.44	7
	Group 3	116.29 ± 91.27	7
	Group 4	173.75 ± 92.66	8
Trial 2	Group 1	264.86 ± 78.49	7	0.13
	Group 2	235.57 ± 103.92	7
	Group 3	173.00 ± 123.25	7
	Group 4	280.00 ± 34.20	8
Trial 3	Group 1	219.86 ± 91.57	7	0.34
	Group 2	204.86 ± 109.06	7
	Group 3	156.71 ± 128.97	7
	Group 4	252.38 ± 69.05	8

ANOVA (F) test was used for statistical comparisons.

Inflammation findings

Comparison of IL-1β levels ​​in the hippocampus of the groups was shown in Table 4. The analysis revealed no statistically significant differences in hippocampal IL-1β (pg/mL) levels among the groups (p = 0.13) (Table 4.).

Table 4.

Comparison of IL-1β levels ​​in the hippocampus of the groups.

Group	Mean±SD (pg/mL)	p-value
Group 1	1.413 ± 0.292	0.13
Group 2	0.959 ± 0.066
Group 3	0.987 ± 0.054
Group 4	1.086 ± 0.078

ANOVA (F) test was used for statistical comparisons.

Comparison of TNF-α levels (pg/mL) in the hippocampus of the groups was shown in Table 5. The analysis revealed a statistically significant difference among the groups (p = 0.001). The curcumin-treated group after FC induction (Group 4) had significantly lower TNF-α levels compared to both the control group (Group 1) (p = 0.001) and the FC-induced group (Group 3) (p = 0.04). Similarly, the curcumin-treated group without FC induction (Group 2) showed significantly lower TNF-α levels compared to both the control group (Group 1) (p = 0.001) and the FC-induced group (Group 3) (p = 0.001) (Table 5; Fig. 2).

Table 5.

Comparison of TNF-α values (pg/mL) ​​in the hippocampus of the groups.

Group	Mean±SD (pg/mL)	p-value
Group 1	14.05 ± 0.70	0.001
Group 2	9.95 ± 0.44
Group 3	12.20 ± 0.60
Group 4	10.90 ± 0.25

ANOVA (F) test was used for statistical comparisons.

Fig. 2.

Comparison of TNF-α values (pg/mL) ​​in the hippocampus of the groups (*p < 0.05; **p < 0.001).

Comparison of serum IL-1β and TNF-α values was shown in Table 6. The analysis revealed that serum IL-1β levels did not show a statistically significant difference among the groups (p = 0.40). Similarly, no statistically significant difference was observed in serum TNF-α levels among the groups (p = 0.45) (Table 6).

Table 6.

Comparison of serum IL-1β and TNF-α values.

	Group	Mean (pg/mL)	p-value
IL-1β (N = 7)	Group 4	17.13	0.40
	Group 2	11.36
	Group 3	17.93
	Group 1	13.29
TNF-α (N = 7)	Group 4	15.38	0.45
	Group 2	16.50
	Group 3	10.64
	Group 1	17.43

ANOVA (F) test was used for statistical comparisons.

Febrile convulsion (FC) and Curcumin findings

The comparison of FC onset and termination values among the groups was shown in Table 7. The analysis revealed no statistically significant difference in FC onset values (p = 0.29). However, a statistically significant difference was observed in FC termination values among the groups (p = 0.001) (Table 7).

Table 7.

Comparison of febrile convulsion (FC) onset and termination values among the groups.

	Measurements	Group 4 (FC + Curcumin)	Group 3 (FC)	p-value
		Mean±SD (s)	Mean±SD (s)
FC Onset	1	107 ± 65	70 ± 27	0.29
	2	99 ± 42	84 ± 38
	3	91 ± 30	109 ± 68
	4	99 ± 24	98 ± 19
	5	91 ± 23	85 ± 18
	6	69 ± 13	85 ± 18
	7	73 ± 21	69 ± 14
FC Termination	1	56 ± 29	77 ± 28	0.001*
	2	61 ± 44	100 ± 40
	3	79 ± 35	115 ± 64
	4	83 ± 51	112 ± 49
	5	43 ± 11	172 ± 54
	6	16 ± 12	174 ± 76
	7	26 ± 24	197 ± 86

ANOVA (F) test was used for statistical comparisons.

Discussion

This study investigated the effects of curcumin administration on neuroinflammation and cognitive function in a FC model in rats. Our findings demonstrate that curcumin significantly reduces hippocampal TNF-α levels following FC and improves learning performance.

FCs are seizure episodes associated with fever, typically occurring between 3 months and 5 years of age, without intracranial infection or a defined seizure etiology. FCs are common in childhood, with a prevalence of 2–5%²¹. Hyperthermia induces changes in neuronal ion channel function, the amplitude of primary ionic currents, and neuronal electrical activity, leading to increased neuronal firing rate, intensity, and synchronization, which in turn triggers seizures²². Recurrent convulsions can cause permanent damage to certain brain structures, leading to hippocampal sclerosis and memory dysfunction²³. In this context, this study focuses on hippocampal inflammation and cognitive function alterations following FC, evaluating the neuroprotective and anti-inflammatory effects of curcumin. Our findings reveal a significant reduction in hippocampal TNF-α levels and an improvement in cognitive performance following FC, supporting the potential of curcumin to mitigate FC-induced neuroinflammation and preserve learning functions.

Curcumin has become a widely used compound in recent years due to its anti-inflammatory and antioxidant properties in neurological disease models^24,25. It is known to exert neuroprotective effects by suppressing inflammation through the inhibition of the TLR4/NF-κB signaling pathway²⁶. A study conducted by Atabaki et al. demonstrated that curcumin reduces neuroinflammation in rats exposed to febrile convulsions by downregulating TLR4 protein expression and preventing lipid peroxidation, thereby exhibiting anticonvulsant effects²⁷. However, to date, no additional studies investigating the relationship between curcumin and febrile convulsions have been identified in the literature. In a limited studies conducted in mice, curcumin was found to alleviate seizure severity and memory impairments in a pentylentetrazol-induced febrile convulsion model. These effects were attributed to central monoaminergic modulation, reduction of nitrosative stress, and inhibition of acetylcholinesterase activity^28–30. This study is one of the few that examines the effects of curcumin on neuroinflammation and cognitive function following febrile convulsions, contributing valuable insights into its potential neuroprotective mechanisms.

In this study, the effects of curcumin administration on learning and memory functions in rats subjected to FC were evaluated using the MWM test. A significant reduction in platform search time was observed in the curcumin-treated FC group, whereas no significant change was detected in the untreated FC group. These findings suggest that curcumin may enhance learning and memory functions through its neuroprotective and anti-inflammatory effects. Atabaki et al. reported that maternal curcumin administration reduced neuroinflammation and improved memory function in offspring following recurrent FC episodes. Their study demonstrated that curcumin exerts neuroprotective effects by inhibiting the TLR4/NF-κB signaling pathway, thereby suppressing inflammation and mitigating the adverse cognitive effects of FC²⁷. Ahmadabady et al. reported that curcumin improved learning and memory impairments in a juvenile hypothyroidism model. These effects were attributed to reducing oxidative stress in brain tissue, lowering nitric oxide levels, and enhancing brain-derived neurotrophic factor (BDNF) production, suggesting a potential neuroprotective role for curcumin in cognitive dysfunction³¹. These findings are consistent with current study, which demonstrated that curcumin administration following febrile convulsions improves learning and memory functions. The anti-inflammatory and antioxidant properties of curcumin may contribute to preserving cognitive function by reducing neuroinflammation and supporting synaptic plasticity.

In this study, the MWM test revealed that group 4 (FC + curcumin) found the platform significantly faster and with less distance traveled compared to group 3 (FC only). Additionally, both group 2 (curcumin-treated control) and group 4 showed a progressive reduction in platform search time over consecutive days, indicating a significant improvement in learning performance. These findings support the positive effects of curcumin on learning and memory functions. Ahmadabady et al. reported that curcumin improved learning and memory impairments in a juvenile hypothyroidism model, and these effects were attributed to its ability to reduce oxidative stress in brain tissue, lower nitric oxide levels, and enhance BDNF production, suggesting a neuroprotective role for curcumin in cognitive dysfunction³¹. Changlek et al. investigated the protective effects of curcumin against lead-induced neurotoxicity and found that curcumin improved learning and memory functions by reducing oxidative damage, inflammation, and cholinergic dysfunction. These studies demonstrate that curcumin’s neuroprotective, anti-inflammatory, and antioxidant properties contribute to cognitive enhancement³². In current study, in the probe trial of the MWM test, curcumin-treated groups (Groups 2 and 4) exhibited a slight reduction in the time spent in the target quadrant (S3) compared to controls. Although curcumin is known for its antioxidant and cognitive-enhancing effects, this minor decrease may reflect inter-individual differences in exploratory behavior or swimming patterns rather than cognitive impairment. Moreover, the absence of statistically significant differences between groups further supports the interpretation that curcumin treatment does not negatively affect spatial memory. Nevertheless, future studies should consider additional behavioral parameters to confirm this interpretation.

The Rotarod test is a widely used technique for assessing motor coordination deficits associated with basal ganglia and cerebellar damage, as well as for evaluating the effects of pharmacological interventions. In this study, Rotarod test results showed no statistically significant differences between groups, suggesting the absence of overt motor function impairments. However, it was observed that Group 4 (FC + Curcumin) exhibited slightly higher performance compared to Groups 1 and 2 in the second and third trials. Although these differences did not reach statistical significance, they may reflect enhanced motor learning or adaptive responses due to repeated exposure to the test conditions. Furthermore, curcumin’s established anti-inflammatory and neuroprotective effects might have facilitated better neuromuscular coordination or faster recovery from trial-induced fatigue. Nevertheless, these results indicate that performance differences observed in the MWM test were primarily related to spatial memory rather than motor deficits. A similar study by Xu et al. investigated the effects of vagus nerve stimulation (VNS) combined with curcumin in a cerebral ischemia/reperfusion (CI/RI) model and reported improvements in cognitive and motor functions; however, their Rotarod test also did not reveal statistically significant differences between groups, consistent with our findings³³. Future studies incorporating more sensitive measures of motor learning and coordination could further clarify these observations.

In this study, the effects of curcumin on FC were evaluated by analyzing FC onset and termination times. In the curcumin-treated FC group, a significant reduction in FC termination time was observed from the third day onward, reaching its minimum level by the fifth day. This finding suggests that curcumin may be effective in shortening FC duration. Kumar et al. investigated the antiepileptic effects of curcumin in an iron-induced epilepsy model, focusing on its impact on voltage-gated sodium channel subtypes Nav1.1 and Nav1.6. Their study demonstrated that curcumin administration reduced epileptiform activity, particularly by downregulating the mRNA and protein levels of Nav1.1³⁴. These findings indicate that curcumin’s antiepileptic effects may be associated with the downregulation of Nav1.1 expression. Rusconi et al. reported that mutations in the SCN1 A gene, which encodes the Nav1.1 sodium channel, lead to functional impairments that contribute to epileptic syndromes. These mutations disrupt intracellular trafficking and function of Nav1.1, resulting in increased epileptiform activity³⁵. These literature findings align with this study, which demonstrated that curcumin reduces FC termination times. The potential mechanism underlying this effect may involve curcumin-mediated downregulation of Nav1.1 expression, thereby reducing epileptiform activity and shortening FC duration.

In this study, we observed that serum IL-1β levels were highest in the FC-induced group, while they were lowest in the curcumin-treated groups. These findings are consistent with existing literature. Atabaki et al. reported that maternal curcumin administration reduced neuroinflammation and improved memory function in offspring following repeated FC episodes. Their study demonstrated that curcumin exerts neuroprotective effects by inhibiting the TLR4/NF-κB signaling pathway, thereby suppressing inflammation²⁷. Erfani et al. found that curcumin significantly reduced seizure frequency and serum IL-1β levels in pediatric patients with drug-resistant epilepsy, further supporting its anti-inflammatory properties and potential role in seizure control³⁶. These findings align with this study, in which high IL-1β levels were observed in the FC-induced group, whereas lower IL-1β levels were detected in the curcumin-treated groups. However, in this study, serum IL-1β levels were measured nine days after FC induction, and the lack of a statistically significant difference between groups may be due to the natural decline in acute inflammation over time.

In this study, we observed that hippocampal TNF-α levels were significantly lower in the curcumin-treated groups, supporting the hypothesis that curcumin reduces TNF-α production by inhibiting NF-κB pathways. This finding aligns with previous research demonstrating curcumin’s anti-inflammatory properties. Jobin et al. reported that curcumin inhibits cytokine-mediated NF-κB activation and suppresses pro-inflammatory gene expression. Their study showed that curcumin blocks NF-κB activation by inhibiting IκB kinase activity, leading to a reduction in TNF-α production³⁷. Aggarwal et al. demonstrated that curcumin inhibits the expression of TNF-α and other pro-inflammatory cytokines, and that this effect is closely related to NF-κB pathway suppression³⁸. These studies support the role of curcumin in reducing inflammation and TNF-α production. Our findings are consistent with these reports, further confirming that curcumin lowers TNF-α levels through NF-κB inhibition, reinforcing its potential as a neuroprotective and anti-inflammatory agent.

In this study, while hippocampal TNF-α levels significantly decreased in curcumin-treated groups, no statistically significant differences were observed in serum TNF-α and IL-1β levels across groups. This discrepancy may be explained by the timing of serum sample collection, which occurred nine days after febrile convulsion induction. By that time point, systemic inflammatory responses could have naturally diminished, reducing detectability. Furthermore, the blood-brain barrier’s selective permeability may restrict cytokine transfer between central and peripheral compartments, leading to differences between hippocampal and serum cytokine measurements. Future studies with multiple time-point measurements of cytokines could clarify the temporal dynamics of these inflammatory responses.

Limitations of the study

This study provides valuable insights into the neuroprotective and anti-inflammatory effects of curcumin in a FC model, yet certain limitations should be acknowledged. One key limitation is the short-term evaluation, as we primarily assessed acute-phase changes, leaving long-term effects unexplored. Additionally, while we measured hippocampal and serum IL-1β and TNF-α levels, a more comprehensive molecular analysis, including oxidative stress markers and NF-κB pathway components, could provide deeper mechanistic insights. Furthermore, we used a fixed curcumin dose (200 mg/kg/day) for seven days, and dose-dependent or long-term treatment effects were not evaluated. The absence of additional behavioral tests beyond MWM and Rotarod limits a more comprehensive cognitive and motor assessment. Lastly, despite its observed benefits, curcumin’s bioavailability and metabolism in human FC cases require further investigation before clinical application.

Despite these limitations, this study has notable strengths. It is among the first to evaluate curcumin in an FC model, providing novel insights into its neuroprotective properties. By combining biochemical and behavioral assessments, we offer a multi-faceted evaluation of curcumin’s effects on inflammation and cognition. The well-established 44 °C water bath FC model ensures reproducibility, and our findings align with previous studies highlighting curcumin’s role in modulating neuroinflammation and oxidative stress, reinforcing its therapeutic potential.

Conclusions

This study demonstrates that curcumin administration effectively reduces TNF-α levels, which are elevated due to febrile convulsions, highlighting its anti-inflammatory potential. The significant reduction in hippocampal TNF-α levels supports the hypothesis that curcumin exerts anti-inflammatory and antioxidant effects by mitigating neuroinflammation. Additionally, curcumin treatment significantly shortens febrile convulsion duration, suggesting its potential role in modulating convulsive activity and neuronal excitability. The observed reduction in convulsion termination time further reinforces its therapeutic potential in managing seizure activity. Findings from the Morris Water Maze test indicate that curcumin alleviates convulsion-induced cognitive impairment, as evidenced by shorter platform search times, increased speed, and reduced distance traveled. These results suggest that curcumin enhances memory and learning processes, likely due to its neuroprotective and antioxidant effects. In conclusion, curcumin may serve as a promising neuroprotective agent in febrile convulsions by reducing neuroinflammation, improving cognitive function, and mitigating seizure severity. Further studies are warranted to explore its long-term efficacy and potential clinical applications in pediatric febrile seizure management.

Author contributions

Conceived and designed the experiments: HC, DSK. Performed the experiments: HC, DSK. Analyzed the data: DSK, MO. Wrote the paper: HC. All authors read and approved the manuscript.

Funding

This study was supported by the Scientific Research Projects Management Unit (BAPYB) of Gaziantep University under project number TF.DT.19.60.

Data availability

Data are available with a reasonable request to the corresponding authors.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The rats used in this study were obtained from the Experimental Animals Research Center of Gaziantep University. Ethical approval for the study was obtained from the Gaziantep University Local Ethics Committee for Animal Experiments (2019/32). The research adhered to the Declaration of Helsinki protocol, following the ethical standards outlined in the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical guidelines. 

Consent for publication

Not applicable.