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representative light microphotographs of hematoxylin and eosin-stained sections from the hippocampus of rats treated with vehicle (dimethyl sulfoxide) (A), rotenone (B-C), or rotenone and 20 mg/kg methylene blue (D). Notes: (A) rats treated with vehicle: normal neuronal structure (arrow). (B) rotenone: darkly stained pyknotic and apoptotic (arrowhead) cells. (C) rotenone: higher magnification image showing darkly stained degenerated neurons (arrowhead) and a reduced number of neurons (arrow). (D) rotenone with methylene blue: less neurodegeneration with few pyknotic (long arrow) and aopototic (arrowhead) cells.
Source publication
Omar ME Abdel-Salam,1 Enayat A Omara,2 Eman R Youness,3 Yasser A Khadrawy,4 Nadia A Mohammed,3 Amany A Sleem51Department of Toxicology and Narcotics, 2Department of Pathology, 3Department of Medical Biochemistry, 4Department of Medical Physiology, 5Department of Pharmacology, National Research Centre, Cairo, EgyptAbstract: This study investigated t...
Contexts in source publication
Context 1
... hippocampal region in control rats showed normal cellular composition in all layers (molecular, Purkinje, and granular, Figure 6A). Following rotenone injection, hip- pocampal neuronal cells showed fewer histopathological changes compared with those seen in the cortex and striatum. ...
Context 2
... apoptotic cells were observed, as well as degenerated and necrotic cells. Neuronal cells with dense pyknotic nuclei were also seen ( Figure 6B and C). Methylene blue 20 mg/kg decreased this neuronal degeneration, with only small neuronal loss in the hippocampus being seen as compared with the rotenone only group ( Figure 6D). ...
Context 3
... cells with dense pyknotic nuclei were also seen ( Figure 6B and C). Methylene blue 20 mg/kg decreased this neuronal degeneration, with only small neuronal loss in the hippocampus being seen as compared with the rotenone only group ( Figure 6D). striatum, and hippocampus) quantitatively ascertained that the area of damage was significantly greater in the rotenone group than in the control group. ...
Citations
... Neurotransmission in cholinergic system is terminated by AChE by hydrolyzing acetylcholine to acetate and choline. Decrease in AChE activity is observed in the hippocampus and cortex of the brain of rotenonetoxified rats in the present study and inhibition of AChE activity has been reported to aggravate motor dysfunction in rotenone neurotoxicity [58]. An increase in hippocampal and cortical AChE activity by taxifolin could assuage motor, cognitive and memory impairment induced by rotenone toxicity. ...
... Oxidative stress has been demonstrated as a major pathology in neurotoxicity induced by rotenone. In rodents, subcutaneous exposure to rotenone increased the generation of reactive oxygen species in many brain regions such as cortex, hippocampus and striatum [58,61]. Glutathione is an endogenous non-enzymic antioxidant, which in its reduced form (GSH) along with other antioxidants, scavenge free radicals and protects the cells from oxidative injury, as well as maintains reduced intracellular homeostasis. ...
... Images were examined under the same magnification by an investigator blinded to the test group. 25 ...
Introduction
A recent approach to cure neurodegenerative diseases is to reprogram fibroblasts into functioning neurons using multiple exogenous transcription factors (TFs) and micro‐RNAs. Administering agents that can endogenously induce these TFs may bypass the limitations of this approach. Astrocytes may represent a part of the extrahepatic‐stellate system involved in vitamin‐A (VA) homeostasis. Activated‐stellate cells lose their VA‐storage capacity, and this was previously applied for hepatic‐stellate cells (HSCs) targeting to treat liver fibrosis. Accordingly, it is hypothesized that Parkinson's disease (PD) may be coupled with retinoid depletion that may extract VA from VA‐rich‐HSCs triggering liver fibrosis. Thus, VA administration may selectively target VA‐deficient reactive astrocytes and HSCs. Besides, VA has the regenerative capability and may induce endogenous‐TFs generation.
Methods
Fluorescently labeled VA‐coupled liposomes (FLV) were traced using confocal laser microscope in rats with induced PD for detecting brain accumulation and uptake into fluorescently labeled astrocytes. Liver fibrosis associated with PD was assessed biochemically and histopathologically, while VA deficiency was confirmed by assessing retinol‐binding protein gene expression in the brain and liver. Multiple VA doses were tested for reversing PD‐associated liver fibrosis, generating TFs (involved in reprograming astrocytes/fibroblasts into different neuronal types) and capability of dopaminergic‐neurons regeneration.
Results
Fluorescently labeled VA‐coupled liposomes revealed selective brain accumulation and uptake into astrocytes. PD was associated with significant liver fibrosis and VA deficiency in the brain and liver. Furthermore, VA‐medium dose (VAMD) was the optimum one for reversing PD‐associated liver fibrosis, generating multiple astrocytes/fibroblasts reprogramming TFs, regenerating dopaminergic neurons, and improving PD.
Conclusion
VA‐medium dose pursued brain targeting in PD with the potential capability of regenerating neurons and restoring dopaminergic transmission. This may place this therapy as an essential treatment in PD management protocol.
... The present study also shows increased brain nitric oxide (NO) levels following rotenone injections. This observation is consistent with other published studies (34,35). Under physiological conditions, brain NO has an important role as a neurotransmitter and vasodilator. ...
... We have shown that curcumin treatment was shown to maintain the number and size of pigmented dopaminergic substantia nigra neurons. Rotenone produces loss of tyrosine hydroxylase positive neurons and decreases immunohistochemical expression of tyrosine hydroxylase in substantia nigra and striatum (25,35). Curcumin was able to attenuate the rotenone-induced depletion in striatal tyrosine hydroxylase content. ...
Objectives:
Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied.
Materials and methods:
Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included.
Results:
Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline.
Conclusion:
These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.
... In addition, pCA was able to reduce apoptotic cell death by elevating Bcl-2 expression (Sabitha et al. 2019), and it had an inhibitory effect on caspase-3 and caspase-9 activities (Guven et al. 2015), as well as ERK and Akt signaling pathways activation (Vauzour et al. 2007). Although the present study did not observe apoptotic parameters as represented by the previous reports, the neuronal character of rotenone-induced neurodegenerative changes, such as pyknotic and apoptotic nuclei as well as neuropil vacuolation (Omar Me et al. 2014), was indicated. We found most of these neurodegenerative forms in both the SNc and striatum in the Rot-veh group but not in the Sham-veh or Rot-pCA100 groups (Fig. 4). ...
The paper examines the use of natural antioxidant and anti-inflammation substances as therapeutic candidates for brain disease. Para-coumaric acid (pCA), a phenolic compound with a variety of medicinal properties, was used against deterioration caused by various diseases. Recently, pCA has gained attention for use against cardiovascular disease but less so for neurodegenerative disease (i.e., Parkinson’s disease). Therefore, the present study intended to investigate the effect of pCA against rotenone-induced Parkinson’s disease-like pathology in mice. Thirty male institute of cancer research (ICR) mice were randomly divided into three experimental groups: Sham-veh, Rot-veh, and Rot-pCA100. Rotenone (Rot) 2.5 mg/kg was subcutaneously injected every 48 h in the rotenone groups. Alternately, a 100 mg/kg pCA dose was given every 48 h via intragastric gavage to the Rot-pCA100 group for 6 weeks. Motor ability was assessed at the second, fourth, and sixth week before brain collection for biochemical and histological analyses. Results indicated significant motor deficits appeared from the second to sixth week after rotenone injection. Brain analysis detected a significant effect of rotenone in the increase of malondialdehyde and tumor necrosis factor-alpha (TNF-α). This result was observed in accordance with a reduction of tyrosine hydroxylase (TH) and an increase of neuronal degeneration in the substantia nigra par compacta (SNc) and striatum. However, pCA was able to reverse all of the deterioration (i.e., reduced malondialdehyde and TNF-α) rotenone had caused, and it protected against TH and neuronal loss in the SNc and striatum. Therefore, the present study has depicted the neuroprotective effect of pCA against rotenone-induced Parkinson’s disease-like pathology in mice. Benefits of pCA include anti-lipid peroxidation and anti-inflammatory effects, inhibition of neurodegeneration, and a nurturing effect on the TH level in the SNc and striatum, leading to mitigation of motor deficits.
... In MB-treated mice with ischemic brain injury, the levels of p53 and Bax were decreased, but the content of Bcl-2 was elevated [85]. MB also downregulated Bax, while upregulating Bcl-2 in the TNBS-induced colitis [74] and rotenone-induced nigrostriatal damage [101]. It appears that MB interacts indirectly with Bcl-2 and Bax. ...
... It appears that MB interacts indirectly with Bcl-2 and Bax. Most likely, it affects the levels of the pro-and anti-apoptotic factors by inhibiting TNF-α [100,101] or preventing the emergence of mitochondrial dysfunctions. For example, MB suppressed the opening of mitochondrial pore [102]. ...
... MB reduced the amount of cytochrome c in the cytosol and decreased the activity of caspase-3 [26,27,[101][102][103][104], caspase-6 [104,105], caspase-8 [26,103], caspase-9 [27,102], and caspase-1 responsible for pyroptosis [106]. For caspase-1, caspase-3, and caspase-6, it was shown that MB can directly oxidize their catalytic domains and inhibit their activity [103] (Fig. 5). ...
Methylene blue (MB) is the first fully synthetic compound that had found its way into medicine over 120 years ago as a treatment against malaria. MB has been approved for the treatment of methemoglobinemia, but there are premises for its repurposing as a neuroprotective agent based on the efficacy of this compound demonstrated in the models of Alzheimer's, Parkinson's, and Huntington's diseases, traumatic brain injury, amyotrophic lateral sclerosis, depressive disorders, etc. However, the goal of this review was not so much to focus on the therapeutic effects of MB in the treatment of various neurodegeneration diseases, but to delve into the mechanisms of direct or indirect effect of this drug on the signaling pathways. MB can act as an alternative electron carrier in the mitochondrial respiratory chain in the case of dysfunctional electron transport chain. It also displays the anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS), activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins. Comprehensive understanding of all aspects of direct and indirect influence of MB, and not just some of its effects, can help in further research of this compound, including its clinical applications.
... In the experimental rotenone model, it is seen that rotenone causes an increase in oxidant capacity and a decrease in antioxidant capacity (20,40,(42)(43)(44). Rotenone provides a role in neuronal loss by causing damage due to oxidative stress by being a specific complex I inhibitor to increase oxidative stress-mediated neuropathology in the pathogenesis of Parkinson's. ...
Parkinson's disease (PD) is a progressive neurodegenerative disorder of the central nervous system. In different studies, it has been investigated that boric acid has positive effects on different mechanisms that are important in PD. The aim of our study was to investigate the pharmacological, behavioral and biochemical effects of boric acid on rats with experimental PD with Rotenone. For this purpose, Wistar-albino rats were divided into 6 groups. Only normal saline was applied subcutaneously (s.c) to the first control and sunflower oil to the second control group. Rotenone was administered (s.c) to 4 groups (groups 3-6) at a dose of 2 mg/kg for 21 days. Only rotenone (2mg/kg, s.c) was administered to the third group. Boric acid was administered intraperitoneally (i.p.) at 5 mg/kg, 10 mg/kg, and 20 mg/kg to groups 4, 5, and 6, respectively. During the study, behavioral tests were applied to the rats, and then histopathological and biochemical analyzes were performed from the sacrificed tissues. According to the data obtained, a statistically significant difference (p<0.05) was observed between the Parkinson's group and the other groups in motor behavior tests, excluding the catalepsy test. Boric acid exhibited dose-dependent antioxidant activity. As a result of the histopathological and immunohistochemical (IHC) examination, a decrease in neuronal degeneration was observed at the increasing doses of boric acid, while gliosis and focal encephalomalacia were rarely encountered. There was a significant increase in tyrosine hydroxylase (TH) immunoreactivity, especially in group 6, with a dose of 20 mg/kg of boric acid. From these results, we conclude that the dose-dependent effect of boric acid may protect the dopaminergic system with antioxidant activity in the pathogenesis of PD. However, the effectiveness of boric acid on PD needs further investigation in a larger, more detailed study using different methods.
... 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. ...
... Thus, anticholinergic medicines may help alleviate disease symptoms, especially the related tremor. 33 Reducing AChE activity is likely to aggravate PD motor characteristics. ...
... 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. ...
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.
... Each of these enzyme systems can generate ROS (Comporti et al., 2010;Osna et al., 2017). Previous studies showed that tissue damage induced by acute EtOH is associated with increased oxidative stress (Aksu et al., 2010;Abdel-Salam et al., 2014). Acute EtOH administration increased lipid peroxidation in rat hippocampus (Gönenç et al., 2005). ...
Ethanol (EtOH) intake is an important global health problem which affects many organs such as the brain, liver and stomach. The aim of the study was to examine the effect of the redox dye methylene blue (MethyB) on oxidative stress and histologic damage to the liver, gastric mucosa, and brain induced high dose ethanol (EtOH). Male rats were treated with EtOH (2 ml/rat, 96%) via intragastric route (for two consecutive days). MethyB (20 or 40 mg/kg, intraperitoneally) was given immediately after EtOH administration. The control group received saline. Rats were euthanized three hours after the last treatment. Brain and liver levels of malondialdehyde (MDA), reduced glutathione (GSH), and paraoxonase-1 (PON-1) as well as brain 5-lipoxygenase (5-LOX) and butyrylcholinesterase (BChE) were determined. Histopathological assessment of brain, liver and gastric damage was done. Results indicated that compared to saline treated animals, EtOH caused significant increase in MDA, along with decreased GSH and PON-1 activity in brain and liver. Additionally, it significantly increased 5-LOX and decreased brain BChE activity. The EtOH group showed the presence of dead and red neurons, and damage of glial cells. The liver exhibited vacuolar degeneration, apoptotic hepatocytes and foci of necrosis. The gastric mucosa showed areas of tissue damage, mucosal atrophy, and loss of normal architecture of glandular cells. The EtOH induced biochemical and histopathological alterations were alleviated after treatment with MethyB at a dose-dependent manner. These results demonstrate that MethyB is able to protect against from acute effects of EtOH on brain, liver and gastric tissue via an antioxidant action. MethyB might be of value in reducing tissue injury in acute EtOH intoxication.
... In the current study, rotenone-treated rats showed significantly elevated levels of TBARS, a marker of lipid peroxidation, and decreased levels of enzymatic antioxidant activity in the cortex and hippocampus. This is consistent with previous reports (Verma and Nehru, 2009;Abdel-Salam et al., 2014). Administration of ILF in rotenone-treated rats reducing the levels of lipid peroxidation and enhanced the activity of antioxidant enzymes. ...
Isolongifolene (ILF), a novel tricyclic sesquiterpene compound isolated from the Indian herb Murraya koenigii (M. koenigii), has been previously demonstrated to have a neuroprotective effect against rotenone-induced oxidative stress, mitochondrial dysfunction, and apoptosis in in vitro model. However, these neuroprotective and anti-apoptotic effects of ILF are not well understood and must be further investigated to elucidate the underlying molecular mechanism of ILF in animal experiments. The objective of this study was to evaluate the neuroprotective effect of ILF on motor impediments, neurochemical variables, anti-oxidative indices, and apoptotic protein expression in a rotenone-induced rat model of Parkinson's disease (PD). PD was induced in male albino Wistar rats via injection of 2.5 mg/kg rotenone for 4 weeks. Rotenone produces PD-like effects by promoting mitochondrial complex I inhibition and microglial activation properties. The protective effect of three different doses of ILF 5, 10 and 20 mg/kg were evaluated for spontaneous locomotion, rotarod performance, and striatal dopamine (DA) content. The results showed that ILF dose-dependently ameliorated the rotenone-induced striatal DA loss and motor impairment from 10 mg/kg. Therefore, we selected 10 mg/kg as the ILF dose for further investigation. Chronic administration of rotenone caused PD-related pathological processes like oxidative stress, and produced a significant decrease in tyrosine hydroxylase (TH), DA transporter (DAT), Vesicular monoamine transporter 2 (VMAT2), and a significant upregulated in α-synuclein and apoptotic protein expression of Bax, Cyt-C and caspases -3, -8 and −9 as well as by decreasing Bcl2 expression. Treatment with ILF 10 mg/kg mitigated oxidative stress in rotenone-treated rats. Furthermore, ILF dramatically alleviated rotenone-induced toxicity and cell death by increasing TH, DAT and VMAT2 expression and reducing the upregulation of α-synuclein, Bax, Cyt-C, caspases -3, -8 and -9. Together, our results confirm that ILF’s protective effect against rotenone-induced PD is mediated through anti-oxidant and anti-apoptotic properties. However, further in-depth investigations on ILF’s anti-inflammatory and mitochondrial protective abilities are needed to establish ILF as a potential drug candidate for the treatment of Parkinson’s disease.
... MB is also known to have a beneficial effect on oxidant status, mitochondrial bioenergetics, and inflammatory and apoptotic signaling pathways [52,53]. In the same context, antioxidant and antiapoptotic actions of MB against rotenone neurotoxicity were noted in brains [54]. This agreed with the histological finding that revealed increased apoptotic signaling, as evidenced by an increase in the area (%) of caspase-3 positive cells in the brains of rats exposed to CuO-NPs. ...
Increasing attention has been paid in the past decade to assessing the toxicological effects of nanoparticles and finding a protectant; thus, the current study aimed to investigate the protective effect of the mitochondria-targeting drug methylene blue (MB) against copper oxide nanoparticle (CuO-NP)-induced neurobehavioral toxicity in rats. For this purpose, twenty rats were allocated to four equal groups (n = 5). The negative control group received distilled water intraperitoneally (IP) and Tween 80 (10 %) orally. The CuO-NP group was given a dose of 100 mg/kg of CuO-NPs, administered orally, and the positive control group was treated with 1 mg/kg MB intraperitoneally (IP). The final group was concurrently exposed to CuO-NPs and MB for 14 consecutive days. At the end of the study, each group was neurobehaviorally blind tested relative to other experimental animals, then brain tissue markers were determined and a histopathological examination was conducted. The results showed that supplementation with CuO-NPs induced neurobehavioral alterations; increased Cu content in the brain; and enhanced lipid peroxidation (malondialdehyde [MDA]), protein peroxidation (protein carbonyl [PC]), and DNA oxidative damage (8-hydroxy-2-deoxyguanosine [8−OH-dG]) compared to other treatments. In addition, a decrease was noted in the mitochondrial dehydrogenases’ (aldehyde dehydrogenase 2 [ALDH2], and glutamate dehydrogenase [GDH]) activity in Cu-exposed rats. The histopathological findings revealed shrunken, pyknotic, and hypereosinophic cortical neurons and increased immune positive brown staining of caspase-3 protein, indicating apoptosis. Co-treatment with methylene blue ameliorated the neurotoxic effects of CuO-NPs; therefore, MB evidently had a powerful modulatory effect against the neurotoxicity of nano-Cu oxide via its antioxidant and mitochondrial protection properties.
