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Polish Journal of Pathology
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vol. 69
Original paper

Effect of sinapic acid on memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats

Pouneh Shahmohamady
Akram Eidi
Pejman Mortazavi
Negar Panahi
Dariush Minai-Tehrani

Pol J Pathol 2018; 69 (3): 266-277
Online publish date: 2018/11/20
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Sinapic acid is a hydroxycinnamic acid-derived polyphenol with 3,5-dimethoxyl and 4-hydroxyl substitutes in the phenyl group of cinnamic acid. It is widely distributed in the plant kingdom and is obtained from various plant foods, such as hazelnut, pea, cabbage, wheat, rye, and brown rice [1, 2]. Scientific studies have revealed that sinapic acid has anti-inflammatory [3], antioxidant [4, 5], antibacterial [6, 7], antihyperglycemic [8], antimicrobial [9, 10], anxiolytic [11], cardioprotective [12, 13], antitumor [14], peroxynitrite scavenging [2], and neuroprotective effects [15, 16].
Alzheimer’s disease (AD) is a type of dementia, which is associated with neurodegeneration due to accumulation of neurofibrillary tangles, senile plaque deposits and neuroinflammation, leading to progressive deterioration in cognition. Various mechanisms of neuronal degeneration have been proposed in AD, including abnormalities in glucose metabolism, reduced glucose utilization, oxidative stress, mitochondrial dysfunction, genetic factors, inflammatory processes environmental factors, apoptosis, etc. These factors may interact and amplify each other in a vicious cycle of toxicity, resulting in neuronal dysfunction, cell dysfunction, and finally cell death [17, 18]. Alzheimer’s disease is the most common form of dementia which is characterized by severe neurodegenerative changes such as loss of neurons and synapses in brain [19]. Alzheimer’s disease is characterized by the cerebral accumulation of extracellular deposits called amyloid plaques that are composed of amyloid β peptides (Aβ) of 38-43 amino acids. Amyloid β plaques are cardinal histopathological hallmarks of Alzheimer’s disease, fundamental to the amyloid cascade hypothesis of the disease, which posits cerebral Aβ accumulation as a crucial early player in disease pathogenesis, ultimately leading to neurodegeneration and dementia [20].
Intracerebroventricular (ICV) administration of streptozotocin (STZ), a glucosamine-nitrosourea compound, at a sub-diabetogenic dose to rodents, has provided a relevant model for AD-type neurodegeneration with cognitive impairment, brain insulin receptor dysfunction, progressive cholinergic deficits, glucose hypometabolism, oxidative stress, neuroinflammation, and neurodegeneration, which share many common features with sporadic AD [21, 22, 23].
As oxidative damage plays a role in the etiology of neurological complications, antioxidant treatment is used as a therapeutic strategy in various neurodegenerative diseases [24, 25]. The present study aims to investigate the effect of sinapic acid on behavioral, biochemical, and histochemical changes in ICV-STZ infused rats.

Material and methods


Sinapic acid and STZ were purchased from Sigma-Aldrich Chemical Company (St. Louis, MO). Streptozotocin was dissolved in artificial cerebrospinal fluid (aCSF: 147 mM NaCl, 2.9 mM KCl, 1.6 mM MgCl2, 1.7 mM CaCl2, and 2.2 mM dextrose; pH 7.4) and sinapic acid was dissolved in 10% Tween 80 [16]. Assay kits for catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA), were purchased from Randox (Crumlin, UK). Tumor necrosis factor α (TNF-α) ELISA kit was obtained from Diaclone (Besançon, France). All other reagents used in this study were of analytical grade. Solutions of the drugs and chemicals were prepared freshly before use.


Male Wistar rats, initially weighing 200-230 g, were used in this study. The animals were housed in groups of 5 per cage in a room with controlled temperature (22 ±2°C), lighting (on, 7 AM; off, 7 PM), and relative air humidity (40-60%). The animals were allowed to have free access to standard laboratory chow and tap water. The diet was purchased from Pars-Dam food service, Tehran, Iran. Experimental procedures including animals and their care were carried out according to institutional guidelines in accordance with national and international laws and the Guidelines for Care and Use of Laboratory Animals in Biomedical Research, as adopted and published by the World Health Organization (WHO) and the United States National Institutes of Health, 1985, No. 85-23. The experimental protocol was approved by the Research Ethics Committee of the Faculty of Sciences, Islamic Azad University.

Intracerebroventricular injection of streptozotocin

Animals were anesthetized using ketamine hydrochloride (100 mg/kg, i.p.) and xylazine (5 mg/kg, i.p.). Their head was placed in position in the stereotaxic apparatus and a midline sagittal incision was made in the scalp. The stereotaxic coordinates for the lateral ventricles [26], were measured as 0.8 mm anterior-posterior to bregma; 1.5 mm lateral to sagittal suture; 3.6 mm dorso-ventral from the surface of the brain. STZ was dissolved in aCSF and slowly infused (1 µl/min) in a volume of 10 µl using a Hamilton microsyringe on days 1 and 3 [27]. In the sham-operated group, ICV injection was performed with of the same volume of aCSF as the STZ treated group.

Experimental design

Sinapic acid was dissolved in 10% Tween 80 and given orally once a day using an orogastric tube for 28 days, starting from 1 h before ICV administration of the first dose of STZ [28]. In the present study, the protective effect of sinapic acid in Alzheimer’s rat model has been investigated. Therefore sinapic acid and STZ were treated simultaneously. Since surgery should be performed for STZ treatment, sinapic acid treatment was performed before surgery (one hour before). The animals were randomly divided into 11 experimental groups of 12 animals each as follows:
Group I: Normal control rats received 1 ml of 10% Tween 80 intragastrically as vehicle.
Group II: Sham-operated control rats that underwent surgery. The animals received aCSF (10 µl) in each ventricle (ICV) on the 1st and 3rd days and were given 1 ml of 10% Tween 80 intragastrically.
Groups III-VI: Normal rats received sinapic acid (2.5, 5, 10, and 20 mg/kg bw) daily using an intragastric tube for 28 days.
Group VII: Alzheimer’s control rats were administered STZ (3 mg/kg, ICV) dissolved in aCSF in a volume of 10 µl in each ventricle on the 1st and 3rd days. The animals received 10% Tween 80 as vehicle for 28 days [25].
Groups VIII-XI: Alzheimer’s rats received sinapic acid (2.5, 5, 10, and 20 mg/kg bw) daily using an intragastric tube for 28 days.
The oral administration volume was 1 ml and the duration of the treatments was 28 days. The animals were carefully monitored daily.

Step-through passive avoidance task

Behavioral test was initiated 28 days after ICV-STZ administration. The experiments were performed between 9:00 am and 4:00 pm in the laboratory at standard optimal conditions. On day 28 after ICV-STZ administration, the rats were tested for memory retention deficits using a passive avoidance apparatus [29]. The apparatus consisted of a two-compartment dark/light shuttle box of the same dimensions (20 × 20 × 30 cm). The two compartments were separated by a guillotine door. The dark compartment had a stainless steel shock grid floor. During the acquisition trial, each animal was placed in the light chamber. After a 60 s habituation period, the guillotine door was opened, and the initial latency of the animals to enter the dark chamber was recorded. Rats with initial latency time more than 60 s, were excluded from further experiments. After the rat had entered the dark chamber, the guillotine door was closed and an electric foot shock (50 Hz, 2 mA, 1.5 s), was delivered to the floor grid using a stimulator for 3 s. Five seconds later, the animal was removed from the dark chamber and returned to its home cage. After 24 h, the retention latency time was measured in the same way as that of the acquisition trial, but the foot shock was not delivered. The latency time and the time in dark compartment (TDC), were recorded to a maximum of 300 s. Short latencies and long TDC indicated poorer retention.

Biochemical analysis

Following the completion of all behavioral tests on day 29, animals were anesthetized, decapitated, and their brains were removed. The hippocampus was dissected from the brain and used for biochemical studies. The dissected hippocampus was homogenized in 10 mM tris-buffer (pH 7.4) containing 50 mM Tris, 1 mM EDTA, 6 mM MgCl2, and 5% (w/v) protease inhibitors. The homogenate was centrifuged at 800 × g for 5 min at 4°C to separate the nuclear debris. The obtained supernatant was centrifuged at 10,500 × g for 20 min at 4°C to assess TNF-α and oxidative stress parameters, including CAT, SOD, GPX, and MDA.
ELISA quantification of hippocampal TNF-α was performed according to Deak et al., method [30]. This assay employed the quantitative sandwich enzyme immunoassay technique according to the manufacturer’s instructions. Furthermore, the homogenates were incubated in duplicate in a 96-well microplate coated with anti TNF-α monoclonal antibody. The absorbance was read at 450 nm.
CAT activity was measured using Aebi method [31]. A 0.1 mLl sample of supernatant was added to a cuvette containing 1.9 mL of 50 mM phosphate buffer (pH 7.0). The reaction was initiated by adding 1.0 mL of freshly prepared 30 mM H2O2. The decomposition rate of H2O2 was spectrophotometrically determined at 240 nm. The CAT activity was expressed as Unit/mg protein.
SOD activity was measured according to the kit directions. A competitive inhibition assay was performed using xanthine-xanthine oxidase-generated O2 to reduce nitroblue tetrazolium (NBT) to blue formazan. One unit of SOD activity was determined as the amount of enzyme required to reduce NBT to 50% of maximum. The maximum absorbance was read at 550 nm and the enzyme activity was expressed as Unit/mg protein [32].
GPX activity was measured using a method based on the reaction between GSH remaining after the action of GPX and 5,5′-dithiobis-2-nitrobenzoic acid to form a complex with maximum absorbance at 412 nm. One unit of GPX activity was determined as 1 mol/l per min decrease in GSH in an enzymatic reaction by 1 mg of protein per min, deducting the effect of non-enzyme-catalyzed reaction [33].
MDA levels were determined using thiobarbituric acid method by spectrophotometrically monitoring MDA-reactive products. The absorbance of the organic layer was measured at 532 nm. Data were expressed as nanomoles of MDA per milligram of protein (nM MDA mg/protein) [34].

Histopathological examination

After completion of behavioral testing on day 29, the animals (6 animals/group) were anesthetized by inhalation of diethyl ether and perfused transcardially through ascending aorta with 100 mL of ice cold phosphate buffered saline (PBS 0.1 M, pH 7.4) followed by 4% paraformaldehyde in cold PBS (0.1 M, pH 7.4). Brains were removed immediately and post-fixed in the paraformaldehyde solution for 48 h. After fixation, the tissue was dehydrated and embedded in paraffin. Coronal sections were evaluated at 1.8-2.0 mm rostral to the optic chiasma. Sections (4 µm) were prepared and subjected to Bielschowsky staining as described in the protocol of the instructions. After staining, the stained hippocampus and cortex sections were examined under a light microscope (Nikon E200, Japan). Neuronal cell count in the cortex, CA1, CA2, CA3, and dentate gyrus of the hippocampus, was performed by Image Analyzer software version 1.36.1.

Statistical analysis

Statistical analyses were carried out using SPSS 10 (SPSS, Chicago, Ill) program for Windows. Data were expressed as mean ± SEM. Data were analyzed using one-way analysis of variance and Tukey’s post-hoc test. The criterion for statistical significance was p < 0.05.


Effect of sinapic acid on memory retention

The initial latency in the acquisition trial showed no difference among the groups. However, after 24 h, retention latency in ICV-STZ control group was significantly lower than normal control rats, indicating impaired learning and memory. Administration of sinapic acid at doses of 10 and 20 mg/kg significantly improved the memory deficits as demonstrated by increased retention latencies. The initial latency showed no significant difference between sham-operated and normal control groups. Interestingly, treatment with sinapic acid (at doses of 2.5, 5, 10, and 20 mg/kg) alone, caused no significant changes in initial latency as compared to the normal control rats (Fig. 1).
The results of the behavioral test showed significant differences in the TDC of passive avoidance response between ICV-STZ control group (rats were administered STZ) and normal control group (rats received Tween 80 as vehicle). The administration of sinapic acid (10 and 20 mg/kg) caused a significant decrease in TDC compared to the ICV-STZ control rats. Also, normal rats treated only with sinapic acid (at doses of 2.5, 5, 10, and 20 mg/kg) did not show any significant difference in TDC compared to normal control and sham-operated groups (Fig. 2).

Effect of sinapic acid on biochemical parameters of brain homogenate

Our results revealed that TNF-α levels were significantly elevated in ICV-STZ group as compared to normal control group. Administration of sinapic acid (10 and 20 mg/kg) significantly inhibited the increase of TNF-α levels in the brain of ICV-STZ rats. No significant difference was observed in the TNF-α level in the animals only treated with sinapic acid (2.5, 5, 10, and 20 mg/kg) compared to normal control rats (Fig. 3).
Our data showed that the activity of antioxidant enzymes (CAT, SOD and GPX) significantly decreased in the ICV-STZ control group compared to the normal control group. However, administration of sinapic acid (at doses of 10 and 20 mg/kg) significantly increased the activity of these enzymes in the ICV-STZ rats. No significant change was observed in sham-operated rats or normal rats received sinapic acid (at doses 2.5, 5, 10, and 20 mg/kg) as compared to the normal control rats (Figs. 4-6). On the other hand, the level of MDA significantly increased in the ICV-STZ control group compared to the normal control group, and treatment with sinapic acid (at doses 10, and 20 mg/kg) significantly and dose dependently decreased the level of MDA in the brain. No significant change was observed in the normal rats only treated with sinapic acid (at doses 2.5, 5, 10, and 20 mg/kg) and sham-operated rats (Fig. 7).

Effect of sinapic acid on histological changes in cerebral cortex and hippocampus

Histopathological changes in neurons following ICV-STZ injection, were assessed by Bielschowsky staining on the cerebral cortex and hippocampus sections. In the ICV-STZ (Alzheimer’s) group, there was a decrease in neuronal population in different regions of the brain and hippocampus, which is associated with gliosis, severe degeneration, and neuritic plaques (an average of 12 plaques in high power field) in the cerebral cortex. Neuronal loss, especially in CA1 area, was seen in the hippocampus. The brain sections of the control normal rats treated with sinapic acid and the sham-operated group, showed no pathological changes in this area. Administration of sinapic acid in Alzheimer’s group at doses of 10 and 20 mg/kg, significantly decreased neuronal degeneration and cell loss in cerebral cortex and hippocampus. In the group treated with the dose of 10 mg/kg, there were 2 plaques and in the group treated with the dose of 20 mg/kg, one plaque with mild gliosis was observed (Fig. 8 and Table I).


In the present study, we indicated that sinapic acid could dose-dependently reduce the changes of behavioral parameters, increase TNF-α levels, increase activities of CAT, GPX, and SOD, decrease MDA levels, and attenuate histological damage in the cortex and hippocampus in the ICV-STZ rats. According to our results, administration of sinapic acid in ICV-STZ rats, caused behavioral, biochemical, and histological improvements. No significant alterations were seen in the normal rats treated with sinapic acid.
In the current study, administration of STZ caused significant behavioral, biochemical, and histopathological changes in rats. It has been reported that ICV-STZ rodent model is an appropriate animal model for the study of sporadic dementia of Alzheimer’s type [35, 36, 37, 38, 39]. ICV administration of STZ in rats leads to impairments in brain biochemistry, cerebral glucose, energy metabolism, cholinergic transmission and increases free radical generation and demyelination, which finally lead to cognitive deficits [35, 40, 41]. Altogether, these effects resemble sporadic dementia of Alzheimer’s type in humans [42]. The exact mechanism of STZ cytotoxicity has not yet been clarified, but it is known that the alkylating effects of STZ metabolites produce reactive oxygen species (ROS), causing oxidative stress and DNA damage. Peripheral administration of STZ (i.p.) is commonly used to generate diabetic model, but ICV-STZ acts through different mechanism from STZ (i.p.), because the oxidative stress caused by STZ (i.p.) and ICV-STZ is not mediated by the same mechanism. This increased oxidative stress may be due to hyperglycemic condition in the brain following STZ administration. Brain slices of ICV-STZ rats showed decreased glucose uptake from incubation medium compared to control rats, which results in hyperglycemia in the brain [43]. In a study by Plaschke and Hoyer [44], increased extracellular glucose was observed in the brain of ICV-STZ injected rats, This may lead to increased nonenzymatic glycosylation of proteins and auto-oxidation of glucose, which results in the generation of advanced glycation end-products. This process leads to subsequent oxidative stress and cellular damage [45].
Our results showed that STZ administration impairs memory recalling without affecting memory acquisition and consolidation in passive avoidance tasks, which is in accordance with earlier studies [46, 47]. Passive avoidance learning refers to learned inhibition of behavior to avoid punishment. Both hippocampus and amygdala are thought to be involved in fear conditioning (passive avoidance) [48]. All these regions of the brain are mainly involved in cholinergic transmission and play vital role in learning and memory processing, and seem to be more prone to oxidative damage [49, 50]. Also, our data indicated that administration of sinapic acid increased memory retention in ICV-STZ rats. In this regard, studies have shown that sinapic acid shows cognitive-improving effects in a CO2– or scopolamine-induced mouse amnesia model [51, 52]. It has been reported that sinapic acid significantly attenuates memory impairment in passive avoidance task. Also, it has been suggested that sinapic acid ameliorates Aβ1-42 protein-related pathology, such as neuronal cell death and cognitive dysfunction through its anti-oxidative and anti-inflammatory activities and may be an efficacious treatment for AD [16].
In line with other studies, our results showed that TNF-α levels increased in hippocampus of ICV-STZ rats [53, 54]. Also, our data showed that administration of sinapic acid could decrease TNF-α level in hippocampus of ICV-STZ rats. These results are similar to those of other studies that believe the link between neuroinflammation and memory deficits [55, 56]. Release of TNF-α and interleukin 1β (IL-1β) initiates inflammatory cascades [57]. Therefore, TNF-α and IL-1β are considered as markers of inflammation in peripheral tissue and brain [56]. Also, some studies believe that TNF-α induces reactive oxygen species toxicity and oxidative stress [58, 59]. The expression of cytokines, generation of free radicals, and neurodegenerative changes are correlated with each other and may contribute to the pathologic process [60]. The antioxidant and anti-inflammatory activities of sinapic acid have been well reported in the literature [3, 61]. It is known that sinapic acid has an anti-inflammatory effect in macrophages through suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and expression of proinflammatory cytokines, such as TNF-α, and IL-1β [3]. Sinapic acid has neuroprotective, free radical scavenging, and anti-inflammatory activities [3], suggesting that sinapic acid could be an appropriate agent for the treatment of AD and other neurodegenerative diseases. Sinapic acid pretreatment significantly alleviates nitric oxide-induced nitrosative stress, leading to reduction of inflammation and vasoconstriction of endothelial cells and prevention of necrosis [62, 63]. Therefore, sinapic acid is an approved potent anti-inflammatory [2, 3] and neuroprotective agent [15, 51].
In the present study, examination of the hippocampal homogenates of ICV-STZ rats, showed a significant reduction in the activities of antioxidant enzymes (SOD, CAT, and GPX) and increased MDA level. Our findings showed that administration of sinapic acid increased the activities of antioxidant enzymes and decreased MDA levels. The alterations in oxidative stress markers and memory deficits in STZ-induced dementia model was similar to the results of Sharma and Gupta [23], suggesting that STZ-induced impairment of learning and memory are associated with oxidative stress in rats. Free radical damage to macromolecules (sugar, lipid, protein, and nucleic acids) accelerates aging and causes age-related neurodegenerative diseases, such as AD [64, 65]. Lipid peroxidation is an indicator of neuronal membrane degeneration. It has been reported that brain lipid peroxidation occurs in early AD [66]. It has also been shown that aging increases lipid peroxidation in the senescence-accelerated mouse brain [67]. MDA is one of the end-products of lipid peroxidation and the key pathogenic factor in biomembrane damage [68]. Increased levels of MDA and decreased levels of antioxidant enzymes (SOD, CAT, and GPX) are considered to be the indicators of oxidative stress. Given that oxidative damage plays a role in the etiology of neurological diseases, treatment with antioxidants is considered as a therapeutic strategy in different neurodegenerative disorders. It has been suggested that sinapic acid is a highly effective radical scavenger with potent antioxidant activity [4, 6, 69]. It is likely that the apparent neuroprotective effect of sinapic acid in the hippocampal CA1 region depends on the sensitivity of the hippocampal CA1 neurons to oxidative stress [70, 71]. It is well-known that sinapic acid has antioxidant and anti-lipid peroxidation activities [12, 72, 73]. In this regard, it has been indicated that sinapic acid reduces lipid peroxidation level and protects cardiac cells from membrane damage through its antioxidant potential. The antioxidant activity of sinapic acid was possible due to the presence of phenolic groups as reported in the literature [61]. It is known that pre-and-co-treatment with sinapic acid normalizes the levels of lipid peroxidation products, thereby inhibiting oxidative stress and stabilizing lysosomal membrane in isoproterenol-induced rats. This effect revealed that anti-lipid peroxidation and membrane stabilizing activities of sinapic acid is due to its free radical scavenging and membrane stabilizing effects [72].
The effect of sinapic acid was also seen on histopathological changes in brain regions of rats treated with STZ. The histopathological changes were examined using Bielschowsky staining in sequential brain sections to determine the extent of damage induced by STZ. Brain sections of STZ-treated rats showed cell loss, neuronal necrosis associated with gliosis and neurofibrillary tangles (NFTs) in the cerebral cortex, and disorganization of hippocampus as compared to normal control and sham-operated groups. STZ caused damage to the hippocampus, especially in CA1 region, and the morphology of cells changed in this particular region as compared to the normal control group. Rai et al. [73] suggest that STZ treatment caused enhanced neuroinflammatory mediators and altered redox stress that contribute to the neurodegenerative processes. These free radicals also further trigger the neuronal damage via formation of pro-inflammatory mediators and associated cytotoxic products during neuroinflammation that can be detrimental to neuronal function. Sinapic acid treatment prevents the damage and causes less damage to the cortical and hippocampal cells compared to STZ-treated rats. These histopathological changes following STZ administration indicate neuronal degeneration in the cortex and hippocampus, which is mainly involved in memory regulation.
In the present study, administration of sinapic acid significantly improves cognitive behavior and biochemical and histopathological changes in ICV-STZ infused rats. Neuroprotective effect of sinapic acid suggests that it is a potent antioxidant, which is in agreement with previous studies [16, 74, 75]. Therefore, these results indicate that sinapic acid could be an effective agent for reducing neurotoxicity through antagonizing oxidative damage induced by ICV-STZ. It has been claimed that sinapic acid can significantly inhibit hypoxia-induced memory impairment [51] and reduce kainic acid-induced hippocampal cell death [15] through its free radical scavenging activity. Also, Zou et al. [2] reported that sinapic acid has a peroxynitrite scavenging effect, and suggested that sinapic acid may play a vital role in the neuronal protection against peroxynitrite-associated diseases. It has been reported that sinapic acid attenuate Aβ1-42 protein-induced activation of microglia and astrocytes. Therefore, sinapic acid is an approved potent anti-inflammatory [2, 3] and neuroprotective agent [15, 51].
In summary, our results confirm that ICV-STZ administration can induce behavioral, biochemical, and histopathological changes due to free-radical generation. Administration of sinapic acid significantly and dose-dependently reduced these changes, which was supported by increase in endogenous antioxidant defense system and decrease in inflammatory responses. These effects may be partly due to its antioxidant and anti-inflammatory activities. The present study showed that sinapic acid can serve as a useful probe in the study of clinical pharmacology of neuronal damage and may be helpful in attenuating oxidative stress and inflammation in neurodegenerative disorders, such as AD.

The authors declare no conflict of interest.


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Address for correspondence

Akram Eidi
Department of Biology
Science and Research Branch
Islamic Azad University
16535 Tehran, Iran
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