Introduction

Diabetes is a major manifestation of endocrine and metabolism disorders and hyperglycemia. Hyperglycemia and methylglyoxal can be implicated in development of micro- and macrovascular complications, which act as a silent killer worldwide [1]. Secondary diseases and long-term complications such as nephropathy, neuropathy, retinopathy and diabetic foot syndrome frequently occur in some diabetic patients [2]. Some factors such as serum uric acid independently predict the development of vascular complications in diabetic patients. Bjornstad et al. indicated that addition of serum uric acid to other risk factors (HbA1c, blood pressure and LDL) would improve the vascular event prediction over 6 years in adults with type I diabetes [3]. Diabetes type I affects pancreatic cells, which are responsible for producing insulin, by inhibiting immune response. However, in type II diabetes, cells become resistant to the use of insulin. Although pathogenesis of diabetes type I and type II is different, defects in insulin secretion and/or action, carbohydrates/lipids and proteins metabolism impairment are some of the main diabetic complications [4]. The number of diabetic patients is on a growing trend, and it is one of the major causes of mortality in most industrial countries [5]. While it was demonstrated that, in a 9-year period study, the regular follow-up diabetes mellitus patients had significantly lower glycemic burden and lower incidence of nephropathy and retinopathy [6], the World Health Organization (WHO) reported that 2.8 % of the global population sustained diabetes in 2000, and they estimated the number of diabetic patients would rise to 4.4 % of the global population by 2030 [7]. Furthermore, 6 % of Iranians aged 20–79 years are suffering from diabetes [8]. Diabetes is recognized as a major cause of cerebrovascular accident, cardiovascular problems, renal failure, atherothrombosis, myocardial infarction, blindness, and non-traumatic lower-limb amputations among the adult population [9]. Increased level of lipids in diabetes may cause cardiovascular complications [9]. Simultaneous decrease in antioxidant agents and mechanisms enhances oxidative stress, produces more free radicals and thereby causes diabetic complications [1012].

In most cases, insulin and oral hypoglycemic drugs are administered as the first-line treatment in diabetic patients [10]. Due to the severe side effects of pharmacologic agents and absence of definitive treatments, researchers are trying to find traditional herbal extracts that have lower toxicity than chemical drugs [11]. On the other hand, for a very long time, medicinal plants were used for treatment of numerous diseases such as diabetes, icterus, cardiovascular problems, hypertension and cancer in traditional ways, especially in Eastern countries. A multitude of studies have been done to investigate the effects of various factors on diabetes management [12, 13]; however, medical knowledge packages for herbal medicines are not efficient enough. According to the previous surveys conducted in the USA and Australia, due to various reasons such as fewer side effects and suitable anti-diabetic properties, almost 50 % (in USA) and around 33 % (in Australia) of population prefer using herbal medicines [14]. Moreover, numerous plants such as garlic, crataegus, cayenne pepper and celery were administered for diabetes in traditional medicine [1518]. Among these plants, celery (Apium graveolens) species, from the family of Apiaceae, has some synergistic beneficial effects on diabetes and hypertension [19], although no toxicologically significant effects have been reported for celery seeds. Moreover, unlike many dietary supplements, the available data suggest that celery seed extract does not significantly affect the enzyme systems and thus is less likely to alter the metabolism of drugs the patient may be taking [20, 21].

Celery leaves are odd-pinnate with dentate leaflets of 3–6 cm long and 2–4 cm wide on a central stem [22, 23]. Among the many constituents of celery, n-butylphthalide (NBP) along with sedanolide provides its aroma and taste, respectively [24]. Some researchers demonstrated that NBP, extracted from other medicinal plants, had some anti-hypertensive effects on animal models [25, 26]. Regarding former investigations, the most active compounds in celery were found in its seeds rather than the other parts (i.e., the roots and leaves) of the plant [27]. Other studies have demonstrated that celery seed and its active ingredients have different therapeutic properties such as hepatoprotective activity [28], cognitive enhancement [29] and antioxidant properties [30].

In our previous study, we exhibited that hexane extract of celery seed has significantly higher level of NBP compared to methanolic and aqueous ethanolic extracts [17]. In the present work, we investigated the anti-hyperglycemic effect of hexane extract of celery seed and its protective properties against pancreatic tissue damage in streptozotocin (STZ)-induced diabetic rats. Different variables including weight, daily water intake, fasting blood sugar (FBS), insulin, triglyceride, cholesterol, high-density lipoprotein (HDL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and histopathology of pancreatic cells and islets was reported.

Materials and methods

Chemicals

The celery seeds were purchased from Imam Pharmacy, Mashhad, Iran, and their identity was confirmed by the herbarium of School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Glibenclamide (Tehran Chemie Pharmaceutical Co., Iran), glucose diagnostic kit, insulin radioimmunoassay kit, triglyceride and cholesterol quantitation kits, HDL quantitation kit, ALT and AST activity assay kits (Pars Azmun Co., Iran), STZ (ENZO Life Sciences, USA), normal saline, ethanol (96 %), liquid paraffin, n-hexane (Merck, Germany), xylazine (Loughrea Corporation, Ireland), ketamine (Retexmedica GmbH, Germany), formalin, distilled water (Hakim Pharmaceutical Co., Iran) and pelleted feed (Javaneh Khorasan Co., Iran) were obtained.

Preparation of the celery seed extraction

Dry celery seeds (50 g) were powdered and suspended in n-hexane (250 ml) at room temperature. The solvent was shaken for 48 h in the dark. Then, it was passed through a cotton filter, the coarse particles were separated, and clear and green suspension remained. Thereafter, the suspension was centrifuged (2594g for about 10 min). The supernatant was separated and evaporated to dryness in the dark at room temperature. Finally, the green oil remained and kept in refrigerator [17].

Animals

Thirty-five adult male Wistar rats (220–270 g), aged 10–11 weeks, were obtained from the animal facilities of the Pharmaceutical Research Center, BuAli Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran. The animals were housed in cage with a 12-h light/12-h dark cycle at 21 ± 2 °C, and free access to food and water was provided for them. The experimental procedures for all the animals were in accordance with the Ethics Committee Acts of Mashhad University of Medical Sciences.

Induction of diabetes by STZ

STZ with chemical formula of 2-deoxy-2-(3-methyl-3 nitrosourea)-d-glucopyranose was used to induce diabetes in the rats. All the groups except group 1 (normal group) intraperitoneally received STZ (80 mg/kg) on day zero (72 h before extract injections). STZ solution was prepared in cold normal saline and was administered to overnight-fasting rats (12 h before injection). On day 3, only those animals with FBS above 200 mg/dl were selected as diabetic animals and were randomized into treatment and negative control groups. Blood samples for checking glucose level were taken from eye orbital plexus.

Experimental design

About 35 rats were randomized into five groups (n = 7) as follows: (1) normal group (not diabetic rats); (2) positive control group [diabetic rats receiving glibenclamide (1 mg/kg) intraperitoneally every other day for 1 month]; (3) negative diabetic control group (receiving 0.5 ml liquid paraffin, as an extract carrier, intraperitoneally every other day for 1 month); (4) and (5) diabetic animals (receiving 100 mg/kg and 200 mg/kg n-hexane extracts intraperitoneally every other day for 1 month, respectively). The animals were fasted from 12 h before blood sampling. Then, they were anesthetized by a mixture of ketamine (60 mg/kg) and xylazine (6 mg/kg), and blood samples were collected from their eye orbital plexus. The blood samples were evaluated on days 3 (the day before STZ injection), 18 and 33. The blood samples were exposed to room temperature for 20 min, centrifuged at 4000 rpm for 10 min and preserved at −20 °C until biochemical assay (biochemistry laboratory in Mashhad University of Medical Sciences) was performed. Different blood serum factors such as FBS, insulin, HDL, cholesterol, triglyceride, ALT and AST were evaluated.

Histopathology

On the final day (day 33), the rats were killed and their pancreas was removed and fixed in buffered formalin 10 % solution for conducting histopathological assay. After processing and embedding, the pancreases were cut into 5-µm slices. The slices were stained with hematoxylin and eosin as the routine staining method. Sliced tissues of each sample were studied at total magnification of 100× and 200×. Different changes in pancreas tissue such as atrophy, necrosis, fibrosis, insulitis and decrease in Langerhans islets were evaluated.

All the qualitative data were changed into quantitative information (Table 4). Scores 0–4 were given to different levels of tissue damage in histopathological evaluations as follows: score zero was considered for normal cells without any damage, and scores one, two, three and four were considered for mild (<25 %), moderate (<50 %), serious (<75 %) and severe (>75 %) damages, respectively.

Statistical analysis

Prism software was employed to analyze the data, and the mean ± SEM were reported. Two-way analysis of variance (ANOVA) and Bonferroni post hoc test were performed for biochemical parameters. The normality test was performed for pathological data. One-way ANOVA and Tukey’s post hoc test were applied for parametric data. Moreover, Kruskal–Wallis and Dunn’s post hoc tests were performed for nonparametric data. P value less than 0.05 was considered significant.

Results

Effects of celery seed extract on weight and daily water intake

Table 1 demonstrates body weight changes in all the groups during the study. Our data showed that body weight in the normal and treatment groups significantly increased after 1 month, whereas a slight increase in body weight was observed in the negative control group. The maximum increase in body weight was observed in the normal and celery extract-receiving groups (200 mg/kg). As shown in Table 2, the initial volume of water intake varied between 35 and 37 ml in all the groups, while the value significantly changed in different groups on day 33. The maximum increase in water intake (59 ml) was seen in the negative control group, whereas the minimum change was reported in the normal (5.5 ml) and positive control (7 ml) groups. The water intake change values (34 and 19.7 ml in groups 4 and 5, respectively) in the groups receiving celery seed extract were significantly different from that of the negative control group.

Table 1 Body weight changes in different groups
Table 2 Water intake changes in different groups

Effect of celery seed extract on FBS

Figure 1 exhibits FBS of the rats during the experiment. No difference was observed between the groups at the beginning of the study, whereas glucose level decreased on days 18 and 33 in all the treatment and positive control groups. The rate of FBS decrease in the positive control group and the groups receiving 200 and 100 mg/kg celery seed extract was 53, 57 and 38 %, respectively.

Fig. 1
figure 1

Fasting blood sugar in normal and streptozotocin-induced diabetic rats in days 0, 3, 18 and 33. The animals were fasted 12 h before blood sampling. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

Effect of celery seed extract on insulin

Table 3 shows the comparison of the level of serum insulin in all the experimental groups on days 0 and 33. As can be noted, insulin concentration in the negative control group significantly decreased, while the normal group did not exhibit any remarkable alterations in insulin level during the experiment. As compared to the negative control group, glibenclamide and celery seed extract (100 and 200 mg/kg) significantly elevated serum insulin concentration in the diabetic rats (P < 0.001).

Table 3 Insulin changes in different groups

Effect of celery seed extract on triglyceride

As shown in Fig. 2, no significant difference was observed between the groups in terms of triglyceride serum level at the beginning of the study. Except for the normal group, a remarkable elevation in triglyceride concentration was noted in all the diabetic groups on day 18. From day 18 to day 33, a significant decrease in triglyceride level was observed in the groups receiving celery seed extract and the positive control group, whereas triglyceride concentration had continuously increased in the negative control group during the study (P < 0.001). On day 33, the minimum triglyceride level was observed in the positive control group, which received glibenclamide. No significant change was reported in the normal group during the study.

Fig. 2
figure 2

Triglycerides serum level in normal and streptozotocin-induced diabetic rats in days 0, 18 and 33. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

Effects of celery seed extract on cholesterol and HDL

Figures 3 and 4 illustrate the changes in serum cholesterol and HDL levels in different groups. Cholesterol level had gradually increased from 67.85 to 72 mg/dl in the negative control group, while this value decreased slowly from 69 to 61 mg/dl in the positive control group. In the groups receiving celery seed extract, cholesterol level increased from day 0 to day 18 and then decreased from day 18 to day 33.

Fig. 3
figure 3

Cholesterol serum level in normal and streptozotocin-induced diabetic rats in days 0, 18 and 33. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

Fig. 4
figure 4

HDL serum level in normal and streptozotocin-induced diabetic rats in days 0, 18 and 33. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

On day 33, no significant difference was observed between the positive control group and the group receiving 200 mg/kg celery seed extract. HDL gradually decreased during the study (from 54 to 45 mg/dl) in the negative control group. However, from day 0 to day 33, HDL level elevated in the other groups. On day 33, no significant difference between the normal and treatment groups (positive control group and the groups receiving celery seed extract) was observed in terms of HDL level.

Effects of celery seed extract on ALT and AST

Figures 5 and 6 show the serum concentrations of ALT and AST in different groups. ALT and AST levels significantly increased after STZ-induced diabetes in the negative control group (P < 0.001). Administration of glibenclamide and celery seed extract prevented elevation of ALT and AST enzymes in the rat serum. The difference between the negative control group and the other groups was statistically significant (P < 0.001).

Fig. 5
figure 5

ALT serum level in normal and streptozotocin-induced diabetic rats in days 0, 18 and 33. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

Fig. 6
figure 6

AST serum level in normal and streptozotocin-induced diabetic rats in days 0, 18 and 33. Glibenclamide was administered as a positive control, and vehicle was administered as negative control. Values are presented as mean ± SD (n = 7)

Histopathology

Histopathological evaluations were carried out to study the effects of celery seed extract on STZ-induced damages to pancreas tissue such as atrophy, necrosis, insulitis, fibrosis and reduction in the number of Langerhans islets (Fig. 7). All the images were presented with two magnifications (100× and 200×). Figure 7a, b demonstrates the normal pancreatic cells and Langerhans islets in the normal rats. As shown in Table 4 and Fig. 7a, b, minimum changes were observed in the normal group. In contrast, maximum damages and pathological scores were reported in the negative control group (Table 4). Figure 7c, d shows a significant decrease in the number of Langerhans islets, necrotic residues of the pancreatic cells and presence of inflammatory cells in the Langerhans islets. Glibenclamide and celery seed extract remarkably reduced the histopathological damages and scores, as compared to the negative control group (P < 0.05). Figure 7e, f illustrates mild inflammatory and degenerative changes in the Langerhans islets of the group receiving 200 mg/kg celery seed extract.

Fig. 7
figure 7

Histopathological evaluations of celery seed extract on streptozotocin-induced damages in pancreas tissue (atrophy, necrosis, insulitis, fibrosis and decrease in the number of Langerhans islets). The normal pancreas cells and Langerhans islets in normal rats with ×100 and ×200 (a, b). Decrease in the number of Langerhans islets, necrotic residues of the pancreas cells and presence of inflammatory cells in islets of Langerhans with ×100 and ×200 (c, d). Mild inflammatory and degenerative changes in islets of Langerhans in 200 mg/kg celery seed extract treated group (e, f)

Table 4 Histopathological study of islets of Langerhans in different groups

Discussion

Diabetes mellitus is a systemic, chronic disease defined as prolonged hyperglycemia and characterized by metabolic disorders of carbohydrates, proteins and lipids. A great number of people suffer from diabetes worldwide [31]. It seems that increasing the free radicals and oxidative stress involved in development of diabetes, whereas the protective agents and mechanisms such as antioxidants are impaired [32]. Methods that induce oxidative stress are usually applied to evaluate hypoglycemic effects of drugs in animal models [33]. In several studies, a single dose of STZ as a glucosamine–nitrosourea compound was used to induce diabetes mellitus in animals by destruction of the pancreatic islets. Intraperitoneal injection of an appropriate dose of STZ causes a reduction in insulin secretion from pancreas due to oxidative damage of Langerhans islets. In this model, insulin is not completely absent but is markedly depleted [34, 35].

Due to the unpredictable side effects and high rate of secondary failure of conventional anti-diabetic agents, the effects of herbal medicines have been evaluated to prevent and control diabetes mellitus [36]. In diabetes mellitus, water intake usually increases, while the rate of weight gain significantly diminishes [32, 37]. In this study, no significant difference was observed between the groups in terms of water intake on the initial day (day zero). After diabetes induction, as expected, water consumption dramatically increased in the diabetic negative control group; moreover, glibenclamide and celery seed extract could decrease water intake in the diabetic animals during the study (in comparison with the negative control). In comparison with the positive control group, the volume of water consumption in the groups receiving celery seed extract was still high on day 33 (P < 0.01), which can be due to the diuretic effect of the active components of celery seed extract. Other studies have also reported antispasmodic and diuretic effects of celery seed extract [17, 38, 39]. Tables 1 and 2 indicate that glibenclamide and celery seed extract could significantly enhance weight gain and decrease the volume of water intake in the diabetic rats compared to the negative control group (P < 0.05 and P < 0.001, respectively). In a study by Al-Sa’aidi et al. [40], body weight in the rats receiving n-butanol extract of celery seed considerably increased compared to diabetic negative control group. In STZ-induced diabetic rats, degradation and loss of structural proteins were the main reasons of body weight reduction [41]. Regarding the previous studies, degradation and loss of structural proteins might have a direct relationship with weight loss in diabetic patients; consequently, active compounds in celery seed may prevent loss of proteins. Other researchers have reported that liver weight decreases with diabetes due to enhanced catabolic processes such as glycogenolysis, lipolysis and proteolysis. The glycogen content in the liver is a storage of glucose and must be considered as an important indicator of diabetes [42]. It was reported that some other herbal extracts such as Nigella sativa might be effective in reducing hyperglycemia and increasing body weight due to its effects on reducing protein loss [43].

The present study showed that administration of celery seed extract from day three to the final day (day 33) significantly lowered serum glucose and prevented insulin depletion in the intervention groups, as compared to the negative control group (P < 0.0001). No significant difference was observed in glucose level of the glibenclamide (1 mg/kg)-administered and celery seed extract (100 and 200 mg/kg)-administered groups on day 33. Serum insulin in the treated rats increased significantly compared to the negative control group, which implies the protective effect of celery seed against oxidative stress and histopathological injuries in pancreas tissue after administration of STZ.

Previous investigations on diabetes mellitus reported that impaired oxidant–antioxidant balance causes oxidative stress, which results in molecular and cellular tissue damage. In other words, increased production of oxygen free radicals (due to non-enzymatic and autoxidative glycosylation) attack macromolecules (nucleic acids, lipids, proteins, and carbohydrates) and cause oxidation injury, which in turn changes oxidant–antioxidant balance in diabetic patients [44]. Moreover, previous studies have suggested a correspondence between the hypoglycemic effects of some medicinal herbs such as Salvia officinalis L., Bridelia ndellensis and Urtica dioica on blood glucose and their antioxidant properties [42, 45, 46]. In addition, antioxidant, cyclooxygenase and topoisomerase inhibitory compounds were found in celery seed by Momin et al. [30, 40]. Lin et al. [47] reported that apigenin and luteolin extracted from celery seed had inhibitory effect on the aldose reductase enzymes (with a key role in the polyol pathway). The polyol pathway appears to be involved in diabetic complications such as nephropathy, retinopathy and neuropathy [48]. Aldose reductase catalyzes the reduction of glucose to sorbitol, which cannot cross the cell membranes, and its accumulation in cells produces osmotic stresses by drawing water into the tissues. Unused glucose enters polyol pathway and reduces to sorbitol [42]. Therefore, apigenin and luteolin in celery seed can lower the microvascular complications of diabetes through inhibition of aldose reductase. Other studies demonstrated that some flavonoids such as apigenin and luteolin, which are present in N. sativa, U. dioica, Punica granatum and celery seed, have antioxidant and protective effects [32, 4953]. Thus, anti-hyperglycemic effects of celery seed may be due to increased secretion of insulin, proliferation of β-cells or increasing their repair after STZ-induced damage, enhanced glucose transport into cells and its utilization by tissues, increased glycogen synthesis from glucose in the liver and improved oxidant–antioxidant balance [54]. Serum glucose level in group 5 (receiving 200 mg/kg celery seed extract) was comparable to that of the positive control group (receiving glibenclamide) on day 33, which indicated the efficacy of the hexane extract of celery seed in lowering blood glucose level.

Additionally, the level of triglycerides in the groups receiving celery seed extract increased from day 3 to day 18, whereas it decreased from day 18 to day 33. In diabetes management, reduction in triglyceride serum level takes a longer duration of time, as compared to serum glucose. This triglyceride reduction pattern was observed in the glibenclamide-administered rats as the positive control. In the healthy rats, lipoprotein lipase is activated by insulin, which hydrolyzes triglycerides; hypertriglyceridemia happens due to insulin deficiency after STZ injection in diabetic rats [55]. Thus, increased insulin concentration reduced deactivation of lipoprotein lipase in the rats receiving celery seed extract and consequently lowered the level of serum triglyceride on the final day [42]. Furthermore, in the previous studies, samples with insulin deficiency were unable to activate the lipoprotein lipase enzyme, which led to hyperglyceridemia [55].

The results showed that the higher dose of celery seed extract (200 mg/kg) significantly lowered the total cholesterol level, while HDL level increased after the administration of 100 and 200 mg/kg celery seed extract. Hypercholesterolemia and HDL reduction were also observed in the negative control group, which indicated dyslipidemia in the diabetic rats. These results imply that celery seed extract administration could effectively improve the metabolism of carbohydrates, lipids and proteins in diabetic patients; metabolic disorders are usually observed in diabetic patients, and hypercholesterolemia and hypertriglyceridemia were observed in the STZ-induced diabetic rats [36, 56, 57]. High level of total cholesterol and low level of HDL play an important role in the incidence of cardiovascular diseases [58]. The effect of celery seed extract was similar to that of glibenclamide. Hypolipidemic effect of celery seed and its bioactive compounds were demonstrated in a former study by Cheng et al. [59]. The hypolipidemic effects of ethanolic extract of celery seed were evaluated by Mansi et al., and their results were in agreement with ours [60]. In a study by Iyer et al., ethanolic extract of celery seed and its chloroform fraction reduced total cholesterol, low-density lipoprotein and triglyceride and increased HDL more significantly than its aqueous fraction in hyperlipidemic rats. Phytochemical evaluations of A. graveolens indicated the presence of tannin, terpenoid, alkaloid, flavonoid, glycosides and sterols, which may be responsible for its hypolipidemic activities [61].

Our results indicated that the rats receiving 100 and 200 mg/kg celery seed extract had stable levels of ALT and AST, whereas these values dramatically increased in the diabetic negative control group. Increased concentration of AST and ALT showed that diabetes may induce liver dysfunction. Quite in line with our results, Larcan et al. found that liver was necrotized in diabetic patients. Elevated ALT and AST concentrations in serum may be due to the leakage of these enzymes from hepatic tissue into the blood [62], which demonstrates the hepatotoxicity of STZ. Therefore, treatment of diabetic rats with celery seed extract could effectively reduce AST and ALT concentrations in rats. Other studies have also reported the protective effect of celery seed extract on liver function and its lowering effect on hepatic enzymes [28, 63]. In the present study, no adverse effect or toxicity was observed after administration of celery seed extract in diabetic rats.

According to our histopathological results, celery seed extract (especially in 200 mg/kg dose) could significantly decrease fibrosis, insulitis, necrosis and atrophy in pancreas tissue compared to the negative control group. It could also prevent attenuation of Langerhans islets (Table 4). These data revealed that active components of celery seed extract could diminish oxidative stress, which was induced by STZ in the diabetic rats. It may also induce regeneration of the islets in the pancreas tissue. Figure 7 shows that the diameter and number of islet cells dramatically increased in the extract-administered groups compared to the negative control group. From the histopathological point of view, treatment with 200 mg/kg celery seed extract could significantly increase regeneration of the pancreatic cells with negligible degeneration and necrosis in the remaining cells compared to the negative control and normal groups. Other studies demonstrated that celery had reasonable amounts of NBP, especially in seeds. Several protective effects of NBP have been reported in previous studies. In a study by Peng et al, inhibitory effects of NBP on lipid peroxidation were reported. Antioxidant activities of NBP may be involved in neuroprotection and treatment of Alzheimer’s disease [29]. NBP has been shown to have anti-inflammatory properties [64]. In an in vitro study, NBP was demonstrated to have protective effects against neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP+) in PC12 cells, which is a cellular model for Parkinson’s disease [65]. Previous works revealed anti-ischemic properties of NBP, which could reduce the risk of cerebrovascular accident and prevent oxidative stress and mitochondrial damages [66]. NBP could also suppress the release of cytochrome C, to induce the up-regulation of vascular endothelial growth factor and subsequently, decrease oxidative stress in diabetic rats [67]. Hepatoprotective effect of celery seed extract against paracetamol and thioacetamide intoxication in rats was previously reported [28]. Singh et al. concluded that stimulation of hepatic regeneration may be involved in hepatoprotective properties of celery seed extract. Other mechanisms such as activation of reticuloendothelial system and inhibition of biosynthesis of some proteins may explain its protective role in different tissue toxicities [28]. Other active components such as apigenin and lutein may explain the protective properties of celery seed extract against oxidative stress and different tissue toxicities [34, 41]. According to the present study and previous reports, antioxidant properties and regeneration stimulating and anti-inflammatory activities of some active components of celery seed extract (e.g., NBP, apigenin, and lutein) may justify its protective effects against STZ-induced pancreatic toxicity.

Conclusion

This study indicated that administration of celery seed extract could significantly reduce water intake and glucose, cholesterol and triglyceride levels in STZ-induced diabetic rats, while it increased serum insulin and HDL compared to the negative diabetic rats. It prevented ALT and AST elevation in the diabetic animals. Histopathological evaluations revealed protective activities of celery seed extract against atrophy, necrosis, insulitis, fibrosis and decrease in the number of Langerhans islets induced by STZ in the diabetic rats.

Different active ingredients such as NBP, apigenin and lutein (through several mechanisms such as antioxidant, anti-inflammatory and regeneration inducing effects) may contribute to protective properties of celery seed extract against STZ-induced pancreatic toxicity. Our results indicated anti-diabetic and anti-hyperlipidemic effects of celery seed extract, which requires further investigation, especially in human samples.