key: cord-0029567-wu8v02v0
authors: Fikry, Heba; Saleh, Lobna A.; Abdel Gawad, Sara
title: Neuroprotective effects of curcumin on the cerebellum in a rotenone‐induced Parkinson’s Disease Model
date: 2022-01-23
journal: CNS Neurosci Ther
DOI: 10.1111/cns.13805
sha: 8eb28bf50ba284bc0a7d493f303ce4b78925eef2
doc_id: 29567
cord_uid: wu8v02v0

AIMS: Parkinson's disease (PD) is the second most prevalent age‐related neurodegenerative disorder. The cerebellum plays a role in PD pathogenesis. Curcumin has numerous medicinal uses, mostly attributed to its potent antioxidant properties. This study investigated the potential protective influence of curcumin on the cerebellum of albino rats with rotenone‐induced PD. METHODS: Forty adult male albino rats were randomized into four treatment groups: vehicle (group I); rotenone 3 mg/kg/day i.p. injection (group II); rotenone 3 mg/kg/day plus curcumin 30 mg/kg/day i.p. injection (group III); and curcumin 30 mg/kg/day i.p. injection (group IV). RESULTS: Compared to group I, group II exhibited marked degenerative changes in hematoxylin & eosin‐stained sections and a reduction in Nissl granules in the Purkinje cells of the cerebellum. In group III, the neurotoxic effects in the cerebellum were reduced. Furthermore, the degenerated Purkinje and GFAP‐positive cells increased considerably in group II and were partially reduced in group III versus group II. Compared to group I, rats in group II showed reduced rotarod motor activity, partially restored in group III. Acetylcholine esterase, glutathione, and superoxide dismutase were significantly reduced, and malondialdehyde was significantly increased in group II compared to group I and was partially increased in group III. CONCLUSION: Curcumin attenuated neurotoxic effects and degenerative histological changes and alleviated induced oxidative stress in the cerebellar cortex of a PD rat model. Therefore, curcumin dietary supplementation may have neuroprotective effects against the development of cerebellum‐related PD symptoms.

Parkinson's disease (PD) is the most common neurodegenerative condition after Alzheimer's disease (AD), affecting about 1% of the population over 65 years old. The number of people with PD is expected to rise from 8.7 to 9.3 million by 2030. 1 PD etiology is unclear, but evidence strongly suggests that chronic neuroinflammation contributes to neurodegeneration. 2 Moreover, selective loss of dopamine neurons and low striatum dopamine levels occur in PD patients. Dopamine deficiency eventually causes dysregulation of basal ganglia circuits, resulting in clinical motive symptoms, including bradykinesia, restless tremor, rigidity, and postural instability. 3 Recently, the role of oxidative stress has attracted increasing attention in neurological abnormalities. Therefore, oxidative stress may also play a role in PD pathophysiology. 4 Pesticide exposure may increase the incidence of PD, as revealed by animal and epidemiological studies. Rotenone is an insecticide and pesticide found in the roots of several plant species. 5 In humans, nasal, dermal, and inhalation routes are the most significant rotenone exposure risks. 6 In addition, rotenone is highly lipophilic and crosses biological mucosa, including the blood-brain barrier (BBB).

Thus, the Parkinson's rotenone model has several advantages over other PD models. 7 The yellow pigment of turmeric and curry (Curcuma longa Linn), curcumin, 1,7-bis (4 Hydroxy-3 Methoxyphenyl), 1,6-Heptadiene-3,5-Dion, or diferuloylmethane, is a well-known polyphenolic compound with preventive properties and therapeutic potential for treating neurodegenerative diseases. 8 Curcumin has a lipophilic property, can pass through cell membranes, and exerts intracellular effects. Curcumin crosses the BBB and is also detected in cerebrospinal fluid. The strong antioxidant properties of curcumin scavenge reactive oxygen species (ROS) and inhibit lipid peroxidation. 9 In one study, administration of curcumin improved behavioral alterations, oxidative damage, and mitochondrial enzyme dysfunction induced by the administration of rotenone in mice. 10 Curcumin also restored electrical activity in the hippocampus altered by rotenone. 11 PD is considered a "classic" basal ganglia disease. Therefore, low dopamine levels in the basal ganglia are the primary focus of experimental and clinical research. However, several studies showed that cerebellar dysfunction and basal ganglia dysfunction are involved in PD-associated motor and non-motor symptoms. 12 Cerebellar dopamine receptors are affected by direct pathogenic alteration via atrophy and denervation. However, greater cerebellar activation occurs during motor execution and during the motor learning process in PD. 13 Enhanced triggering of the cortico-cerebellum motor circuitry is hypothesized to compensate for malfunctioning basal ganglia and regulate motor behavior due to hypoactive cortico-striatal circuitry.

Additionally, increased cerebellar activity may result from the defective subthalamic nuclear pathogenic outflow. 12 The linkage between the basal ganglia and cerebellum provides an anatomical basis for understanding the cerebellum's function in PD and may aid in the development of novel treatment strategies.

Thus, the aim of the present study was to determine the potential protective influence of curcumin on the cerebellum in rotenoneinduced PD in albino rats. 

Forty adult male albino rats weighing 150-200 g (3-6 months) were used. One week before the experiment, the rats were transported to the animal care unit at the Pharmacology Department, Faculty of Medicine, Ain Shams University, for acclimatization to laboratory conditions. The animals were given ad libitum tap water and a commercial diet. The animals were randomly distributed into four experimental groups (10 rats/group). All animal procedures were performed in compliance with the research ethics committee of the Faculty of Medicine, Ain Shams University, Egypt.

In group I (control), rats were treated daily with the vehicle for rotenone and curcumin (DMSO) (1 ml/kg) via intraperitoneal (i.p.)

injection. In group II, the parkinsonism model (rotenone-treated rats), rats were treated with rotenone (3 mg/kg dissolved in DMSO) daily for 60 days. 14, 15 In group III, the curcumin+rotenonetreated group, rats were treated with curcumin (30 mg/kg dissolved in DMSO) and rotenone (3 mg/kg dissolved in DMSO) daily for 60 days. 14 In group IV, the curcumin-only treated group, rats were treated with curcumin (i.p. 30 mg/kg) and DMSO, 1 ml/kg for 60 days.

Rotenone was adapted based on a previous study showing that chronic exposure to rotenone for 28-60 days impaired locomotion. 15 This dose of rotenone is not toxic. The LD50 (lethal to half the experimental animals) is between 132 and 1500 mg/kg for rats. 16 In human clinical trials with doses up to 10 g/day, curcumin was pharmacologically safe. 11 Animals that died after the i.p. injection were excluded from the study.

The rotarod test, in which animals walk on a rotating drum, is widely used to assess laboratory rodent motor status. The rotarod test measures the duration an animal can stay on the drum in relation to the drum speed. Rats were permitted to adjust their postures to retain equilibrium on the rotary rod for at least 60 s at 12 rpm continuously for three experiments with 5 min intervals. The equipment was washed between testing each animal. The average retention time on the rod was determined. 17

After completing the behavioral evaluation, rats were anesthetized with 2 gm/kg urethane (i.p.) and decapitated. Rat brains were rapidly removed, and the cerebellum was isolated and divided into halves.

One half was stored at −80°C for biochemical evaluation, and the other was used for histopathological examination. Moreover, histopathological analyses were used to evaluate neurodegeneration.

The sagittal section of the frontal cerebral cortex, striatum, substantia nigra, and hippocampus were also examined in all groups. For histopathological examination, isolated tissues were fixed immediately in 10% neutral-buffered formalin, processed using a graded ethanol series, and embedded in paraffin. Paraffin sections of 5-7 µm thickness of cerebral and cerebellar hemispheres were stained with hematoxylin and eosin (H&E) stain 18 for routine examination. The Cresyl fast violet stain (Nissl stain) was used to stain Nissl granules in the Purkinje cells' perikarya 19 for paraffin sections of the cerebellar tissue.

TH immunostaining within the substantia nigra pars compacta (a marker for dopaminergic neurons) and GFAP immunostaining within the cerebellum (a marker for astrocytes) were performed. 

For biochemical evaluation, brain tissues from all groups were preserved in PBS at −80°C. The tissues were minced, homogenized, and cooled by the tissue lysate machine with PBS (100 mg tissue/ml).

Samples were centrifuged for 15 min at 1500× g (or 5000 rpm), and then the supernatant was collected and stored at −80°C until assayed. Cerebellar homogenates were used for measuring AChE, lipid peroxidation (by measuring MDA), reduced GSH, and superoxide dismutase (SOD).

AChE activity was measured using an established method modified by Ellman et al. 24 Absorbance was measured at 412 nm. PBS and acetylthiocholine iodide were utilized as reagents. The reaction was stopped with a solution of 5.5′ dithiobis-2-nitrobenzoic acidphosphate-ethanol incubated at 38°C.

Lipid peroxidation forms MDA as a natural byproduct. Thus, a competitive immunoassay technique was used to quantitatively measure MDA in tissue homogenates. The MDA-horseradish peroxidase (HRP) antibody conjugate was added to induce an enzymatic reaction. The color intensity was measured spectrophotometrically. To calculate MDA concentrations, standard curves were created.

GSH levels in tissue homogenates were determined using a rat GSH ELISA kit. The GSH-HRP conjugate was added to initiate the enzymatic response. The strength of color, inversely proportional to the reduced amounts of GSH, was calculated spectrophotometrically.

Standard curves were generated to calculate GSH concentrations.

SOD was determined by pyrogallol oxidation inhibition. 25 An aliquot of the diluted specimen (100 μl) was mixed with 25 μl pyrogallol (24 mmol/L prepared in HCl) to make a volume of 3 ml with Tris HCl (0.1 M, pH 7.8). Absorption changes at 420 nm were measured with a spectrophotometer at 1 min intervals for 3 min. The amount of enzyme that inhibits 50% of pyrogallol autooxidation is a unit of SOD activity. SOD activity was expressed as U/mg.

The Statistical Package for the Social Sciences for Windows (v. 26; IBM Corp., Armonk, NY, USA) was used to analyze the data. Data were expressed as the mean and standard error of the mean (SE).

Tests of normality (Shapiro-Wilk) were used for data distribution assessments. Parametric tests were performed on normally distributed data. One-way analysis of variance (ANOVA) was used to compare various groups, followed by Tukey's multiple comparison test.

Significance was accepted at p < 0.05. GraphPad® Prism Statistical Package Version 9 (2020) was used to visualize the data.

We included ten rats per group. However, two rats died in the rotenone group (group II) and two rats failed to develop PD symptoms.

One rat died and one rat failed to develop PD in group III. No deaths occurred in the other groups. Due to the mortality in groups II and III, additional rats were utilized to keep the number of animals constant (n = 10). All rats were evaluated after they finished the treatment procedure.

The effects of curcumin on rotarod performance are shown in 

To validate the effectiveness of this rat model of PD produced by rotenone, histological examination was performed primarily on the cerebral cortex, striatum, substantia nigra, and hippocampus, as shown in Figures 2, 4 , 5, and 6, respectively.

H&E-stained sections from control group I revealed that the cerebral cortex consisted of six distinguished layers from the outside inward with no sharp boundaries. These layers were: a molecular layer formed of fibers traveling parallel to the surface with relatively few cells, outer granular, outer pyramidal, inner granular, inner F I G U R E 1 Effect of the tested drugs on rotarod performance in different groups. Values are presented as mean ± standard errors (number of rats = 10). ns = non-significant, ****p < 0.0001 pyramidal, and multiform layers. Cortical neurons had a normal appearance, with rounded vesicular nuclei, pale basophilic cytoplasm, and peripheral processes. The neuropil contained astrocytes with sharply demarcated nuclei, and blood vessels with a narrow perivascular space were seen. Rotenone-treated rats showed degenerated shrunken neurons with dark cytoplasm and pyknotic nuclei. Notice hypertrophied astrocytes were also seen. Curcumin-treated rats showed improvement in almost all layers, except some neurons, which appeared with pyknotic nuclei. Curcumin-only-treated rats displayed similar features as the control group ( Figure 2 ).

The control group's striatum exhibited normal neuronal architecture.

Neurons showed round to oval shape with a lesser intensity of staining with clear nuclei. However, in the striatum of the PD rat model, deeply acidophilic irregularly shaped neurons along with vacuolation of neuropils, swelling of neurons, and neuronal degeneration were observed. These histological changes were reduced in the striatum when the rotenone model rats were treated with curcumin.

Curcumin-only-treated rats displayed similar features as the control group ( Figure 3 ).

Normal substantia nigra neurons with nerve cells that are generally multipolar, stellate, or pyriform were seen in sections from the control group. These cells have a basophilic cytoplasm. Astrocytes with clearly defined nuclei and typical organization emerged.

Rotenone-treated rats' substantia nigra displayed high neuronal loss. The cytoplasmic inclusions of Lewy bodies were darkly stained in neurons, and neuronal swelling was observed. When the rotenone model rats were given curcumin, these histological alterations in the substantia nigra were minimized. Curcuminonly-treated rats displayed similar features as the control group ( Figure 4 ).

Sections from the control group showed the normal histological structure of the hippocampus. The CA3 region is divided into three layers: polymorphic, pyramidal, and molecular. The pyramidal layer is made up of three or four rows of tiny pyramidal cells with vesicular nuclei, conspicuous nucleoli, and sparse cytoplasm.

Rotenone-treated rats showed pyramidal cells of the CA3 with signs 

The numbers of degenerated Purkinje cells were significantly differ- Figure 12D ). Figure 12E ).

One-way ANOVA showed significant differences in GSH levels be- shown in Figure 12F . No significant differences in GSH levels were detected between groups III, I, and IV (p = 0.368 and p = 0.335, respectively). Also, GSH levels in groups IV and I were not significantly different (p = 1.00). Also, SOD levels in group III were significantly lower compared with those in groups I and IV (p = 0.05 and p = 0.008, respectively). SOD levels in groups I and IV were not significantly different (p = 0.98) ( Figure 12G ).

Cerebellar interactions with the basal ganglia indicate the cerebellum's key role in the development of PD. 14 According to Wu and Animal pharmacological models serve as invaluable resources for studying the histopathological mechanisms of PD. 26 Rotenone is commonly used in rodent PD models as it induces the pathological symptoms and motor defects of PD. 27 Thus, treatment with rotenone is a feasible way of evaluating the effects of new PD therapeutic agents. The main factor contributing to rotenone's neurotoxic effect is the generation of oxidative stress to produce disease-like pathology. 14 Damaged dopamine-producing cells in the brain are the major cause of PD. The pigmented neurons of the substantia nigra pars compacta of the midbrain degenerate and die selectively. As a result, dopaminergic neuron loss in the substantia nigra pars compacta causes terminal degeneration and dopamine depletion in the striatum, essential for appropriate motor function. 28, 29 In this study, the rotenone group's histological data in the striatum and substantia nigra pars compacta confirmed neuronal necrosis. Additionally, there was a significant decrease in neuronal positivity to TH, indicated by immunohistochemistry in the substantia nigra. Our findings are consistent with previous research. 21, 30, 31 In several studies, TH is the standard method for counting dopaminergic neurons. 32 Shin et al. 29 found significantly decreased motility, gait impairment, and a 50% drop in TH activity in the substania nigra pars compacta. These alterations support the success of this rat model of PD induced by rotenone.

In the present study, brain damage caused by rotenone was not limited to the nigrostriatal pathway. As evidenced by histological inspection, Rotenone injection also caused major degenerative alterations in the cerebral cortex and hippocampus. Our findings are concordant with those of Abdel-Salam et al. 33 who found that rotenone injection caused degenerative alterations in a number of brain locations, including the cerebral cortex, striatum, hippocampus, and substania nigra, resulting from elevated oxidative stress in many brain regions. Curcumin is a strong antioxidant that minimizes oxidative stress in vivo and in vitro. 34, 35 Curcumin exerts various beneficial effects in treating and preventing neurodegenerative diseases, such as stroke and AD. 36, 37 Additionally, several studies demonstrated curcumin's ability to inhibit key PD-associated features, including ROS formation, apoptosis, cytokine production, oxidative damage, and cognitive impairment in cell lines and experimental animals. 38 In this study, behavioral effects were studied using a rotarod test. Compared to control animals, the mean duration of stay in rotarod-induced parkinsonism rats was significantly decreased.

Group III exhibited a significantly increased duration of stay on the accelerating rotarod compared to group II. Ramkumar Most studies suggest a direct relationship between free radicals and microglia, astrocytes, and neurons in neuroinflammatory processes. 42 ROS play a significant role in apoptosis initiation, which increasing antioxidants can block. 43 The present study showed that Immunohistochemical staining confirmed the histological observations in this study. The enhancement of Bergmann astrocytes, indicated by increased expression of GFAP, was apparent after rotenone treatment. Astrocytes react immediately to any nervous system insult by producing neurotoxic substances and GFAP. Thus, GFAP is considered a marker for astrogliosis. 50 GFAP-positive cells increased in group II compared to groups I and III. This might be due to a compensatory mechanism following neurodegeneration. A similar process was reported following neurotoxicity. Astrocytes are involved in neuronal homeostasis, synaptic plasticity, and glial cell activation, resulting in a secondary mechanism of cell death or neuroprotective response. 51 Paul and Borah 48 reported increased GFAP-positive cells, leading to positive and negative outcomes. GFAP-positive cells may protect neural parenchyma against ischemia, inflammation, and neurodegeneration. Unfortunately, glial cells secrete inflammatory cytokines and free radicals, which cause neuronal damage. In this study, curcumin-treated rats showed a significant decrease in the mean number of anti-GFAP stained astrocytes compared to group II.

Our data generally agree with other studies. 52 Increasing data indicate decreased AChE activity in numerous brain disorders, including PD and AD. 48 AChE is also a sensitive enzyme inhibited by increased radical substance formation. Activation of AChE is a critical therapeutic target in treating PD. 14 Additionally, the primary motor symptoms of PD are mostly attributable to a loss of dopaminergic tone and a resulting imbalance in the regulation of striatal output by dopaminergic and cholinergic neurons. Thus, anticholinergic medicines may help alleviate disease symptoms, especially the related tremor. 33 Reducing AChE activity is likely to aggravate PD motor characteristics.

Our results indicate that curcumin treatment in a rat model of PD restored cerebellar AChE activity to nearly the same level as controls, providing an argument for its pathogenic influence on brain functions. Our result is consistent with earlier reports. 33 Interestingly, in the current study, curcumin alone did not negatively affect the test parameters and histologic structures in the cerebellar tissue, in agreement with other studies. 60 Based on the results of this study, rotenone causes Purkinje cell death and astrogliosis by increasing oxidative stress in the cerebellar cortex.

Administration of curcumin prevented these effects. Furthermore, cholinergic neurotransmission alterations induced by rotenone were suppressed by curcumin, thus confirming the behavioral and histological findings.

This shows that curcumin attenuated the neurotoxic effects and degenerative histological changes in the cerebellar cortex and alleviated oxidative stress in a PD rat model. Thus, curcumin could have a role in therapeutic strategies for cerebellar affection related to PD.

The authors would like to thank Enago (www.enago.com) and True

Language Edits editing services for the English language review.

The authors declare that they have no relevant or material financial interests related to the research described in this paper.

The authors confirm contribution to the paper as follows: study con- 

The data that supports the findings of this study are available in the Supplementary Material of this article.

Heba Fikry https://orcid.org/0000-0002-0046-9875

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