Rotenone Administration Research Articles

RETRACTED: Protective effect of roscovitine against rotenone-induced parkinsonism

Protective effect of roscovitine and deregulation of the p-RB/E2F1 have not been well studied in PD models generated by repeated oral administration of rotenone. These experiments evaluated the effects of repeated oral gavage of rotenone on the activation of p-RB/E2F1 and the effects of roscovitine on the regulation of dopaminergic neuronal injury and the behavior of PD in mice. Using 2.5% carboxymethylcellulose and 1.25% chloroform as a vehicle solution, rotenone (30 mg/kg) was administered via oral gavage once daily for 30 days in C57 mice. Behavioral profiles (pole test and traction test) were assessed in these PD models, and oxidative stress levels were evaluated in the midbrain. The immunoreactivities of TH, α-synuclein (α-syn), p-RB, E2F1 and cleaved caspase-3 in the substantia nigra were examined with a laser confocal microscope. Pharmacological inhibition of cyclin-dependent kinase with roscovitine was achieved by intraperitoneal (IP) injection at a dose of 50 mg/kg daily. All rotenone-administered C57 mice showed the typical behavioral features of PD: stiffness, bradykinesia, or hypokinesia. Behavioral testing with the pole test and traction test indicated that the rotenone group, but not the vehicle group, was affected. Spectrophotometric analysis demonstrated that glutathione (GSH) and superoxide dismutase (SOD) activity was decreased, and the generation of malondialdehyde (MDA) was elevated in the midbrain of the rotenone-treated group. After oral administration of rotenone, a loss of nigral tyrosine hydroxylase (TH)-positive neurons was observed. The immune response of α-syn was enhanced in the cytoplasm of dopaminergic neurons from the rotenone-induced neurotoxicity. Rb phosphorylation at serine 780, which affected Rb binding to E2F, was induced after rotenone treatment. The activation of E2F1, which is involved in the regulation of the cell cycle, was also induced from chronic exposure to rotenone. Moreover, administration of the cell cycle inhibitor roscovitine protected against rotenone-induced nigral dopaminergic neuronal injury and inhibited cleaved caspase-3 activation. Roscovitine also markedly ameliorated the behavior of PD mice. Mouse models of Parkinson's disease were established by oral rotenone administration and reproduced some of the features of dopaminergic neuronal degeneration. Roscovitine protects against rotenone-induced parkinsonism.

Neuroprotective effect of agmatine (decarboxylated l-arginine) against oxidative stress and neuroinflammation in rotenone model of Parkinson's disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer's disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and nonmotor symptoms. The neuropathological hallmarks of PD are well reported, but the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, and neuroinflammation play vital roles in the progress of the disease. The current study was established to investigate the neuroprotective effect of agmatine on a rotenone (ROT)-induced experimental model of PD. Adult male Sprague Dawley rats were subcutaneously injected with ROT at a dose of 2 mg/kg body weight for 35 days. Agmatine was injected intraperitoneally at 50 and 100 mg/kg body weight, 1 h prior to ROT administration. ROT-treated rats that received agmatine showed better performance on beam walking and an elevated number of rears within the cylinder test. In addition, agmatine reduced midbrain malondialdehyde as an indication of lipid peroxidation, pro-inflammatory cytokines including tumor necrosis factor alpha and interleukin-1β, and glial fibrillary acidic protein. Moreover, agmatine was responsible for preventing loss of tyrosine hydroxylase-positive neurons. In conclusion, our study showed that agmatine possesses a dose-dependent neuroprotective effect through its antioxidant and anti-inflammatory activities. These findings need further clinical investigations of agmatine as a promising neuroprotective agent for the future treatment of PD.

Zinc and linoleic acid pre-treatment attenuates biochemical and histological changes in the midbrain of rats with rotenone-induced Parkinsonism

BackgroundStudies have suggested the supplementation of Zinc and Linoleic acid in the management of neurodegenerative disorders but none has investigated the combined effects. Little is known about the neuroprotective effects of either Zinc or Linoleic acid or their combination against development of Parkinsonism. This study was designed to investigate the neuroprotective effects of Zinc and Linoleic acid in rotenone-induced Parkinsonism in rats.MethodsThirty-six young adult female rats weighing 100–150 g divided into six groups were used. Rats were induced with Parkinsonism by subcutaneous administration of rotenone (2.5 mg/kg) once a day for seven consecutive days. The rats received dimethyl sulfoxide (DMSO)/Olive oil or rotenone dissolved in DMSO/Olive oil. Groups III and IV received Zinc (30 mg/kg) or Linoleic acid (150 µl/kg) while group V received a combination of both, 2 weeks prior to rotenone injection. Groups II and VI served as negative (rotenone group) and positive (Levodopa groups) controls respectively. Oxidative stress levels were assessed by estimating Lipid peroxidation (MDA), total antioxidant capacity, Superoxide dismutase, reduced Glutathione (GSH), glutathione peroxidase and catalase in the midbrain. Histological examination was done to assess structural changes in the midbrain.ResultsThere was a significant prevention in lipid peroxidation and decrease in the antioxidant status in intervention-treated groups as compared to the rotenone treated group. In addition, histological examination revealed that Parkinsonian rat brains exhibited neuronal damage. Cell death and reduction in neuron size induced by rotenone was prevented by treatment with zinc, linoleic acid and their combination.ConclusionThese results suggest that zinc and linoleic acid and their combination showed significant neuroprotective activity most likely due to the antioxidant effect.

The Effect of Afobazole and Levodopa on Activity of Proline-Specific Proteinases and Adenosine Deaminase in Serum and Brain Structures of Rats with Experimental Parkinsonism Induced by Systemic Administration of Rotenone

The Effect of Afobazole and Levodopa on Activity of Proline-Specific Proteinases and Adenosine Deaminase in Serum and Brain Structures of Rats with Experimental Parkinsonism Induced by Systemic Administration of Rotenone

Early signs of colonic inflammation, intestinal dysfunction, and olfactory impairments in the rotenone-induced mouse model of Parkinson's disease.

The factors that trigger the pathophysiology of Parkinson's disease (PD) are unknown. However, it is suggested that environmental factors, such as exposure to pesticides, play an important role, in addition to genetic predisposition and aging. Early signs of PD can appear in the gastrointestinal (GI) tract and in the olfactory system, preceding the onset of motor impairments by many years. The present study assessed the effects of oral rotenone administration (30 mg/kg) in inducing GI and olfactory dysfunctions associated with PD in mice. Here we show that rotenone transiently increased myeloperoxidase activity within 24 h of administration. Leucocyte infiltration in the colon, associated with histological damage and disrupted GI motility, were observed following treatment with rotenone for 7 days. Moreover, 7 days of treatment with rotenone disrupted olfactory discrimination in mice without affecting social recognition ability. The presence of specific deficits in olfactory function occurred with a concomitant decrease in tyrosine hydroxylase-positive neurons and an increase in serotonin (5-hydroxytryptamine) turnover in the olfactory bulb. These findings suggest that in Swiss mice, exposure to rotenone induces GI and olfactory dysfunction involving immunological and neurotransmitter alterations, similar to early signs of PD. This provides further evidence for the involvement of the gut-brain axis in PD.

P08-Diffusion kurtosis imaging detects early microstructural changes in dorsal motor nucleus of vagus in intragastric rotenone mouse model of Parkinson’s disease

The aim was to determine whether diffusion kurtosis imaging (DKI-MRI) could detect changes in dorsal motor nucleus of vagus (DMV) in mice who received chronic administration of rotenone. This may help in early diagnosis of patients with Parkinson’s disease. Mice received vehicle (VEH) or rotenone (ROT) intragastrically for 4 months. DKI scanning was performed at 2, 3 and 4 months. ROI analysis was used to compare kurtosis and diffusivity parameters in GM regions. WM tracts were investigated using the tract-based spatial statistics. We found significant increase in mean kurtosis in DMV in the ROT group at 2 months. At 3 months we found increase in kurtosis and decrease in diffusivity in almost all regions of interest, showing once the pathology crosses the DMV it spreads throughout the brain. At 4 months all the changes vanished. ROT group showed significant motor impairment at 4 months. At 2 months the DKI parameters may improve the early diagnosis of PD by showing increase in mean kurtosis in the DMV. This may help in monitoring and developing neuroprotective therapy. On the other hand, the lack of the DKI signal changes between ROT and VEH groups at the 4 months probably reflects the brain atrophy.

Neuroprotective potential of spermidine against rotenone induced Parkinson's disease in rats

Parkinson's disease is a leading hypokinetic disorder characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of mid-brain. Degeneration of dopaminergic neurons is considered to be due to oxidative stress, neuroinflammation, disturbed calcium homeostasis and glutamate excitotoxicity etc. Spermidine is a polyamine which counteracts age associated cell death by scavenging free radical formation, activates authophagic machinery by enhancing formation of autophagosome, and antagonizes NMDA receptor. In the current study we investigated the neuroprotective potential of spermidine against rotenone induced PD in rats. Rats were treated subcutaneously with rotenone 1.5 mg/kg daily for 28 days. Spermidine 5&10 mg/kg was administered orally 1 h prior to rotenone administration from 15 to 28. Rotenone caused significant reduction in motor functioning and elevated levels of oxidative stress markers and proinflammatory cytokines levels (IL-1β, IL6 and TNF-α). The neurochemical analysis revealed a significant decrease in serotonin, norepinephrine, dopamine and their metabolites accompanied by a significant loss of dopaminergic neurons in the SNpc following ROT injection. However, treatment with spermidine rescued DAergic neurons in SNpc and nerve terminals in the striatum following ROT insult. Spermidine treatment also attenuated oxidative stress, neuroinflammation and restored striatal neurochemistry. Results of our study suggest that spermidine has promising neuroprotective effect against degenerative changes in experimental PD, and the protective effects are mediated through its antioxidant and anti-inflammatory properties.

Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models

ABSTRACTParkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy.Abbreviations: 6-OHDA, 6-hydroxydopamine; ACTB, actin, beta; BafA1, bafilomycin A1; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B cell leukemia/lymphoma2; BECN1, Beclin 1, autophagy related; CoQ10, coenzyme Q10; COX4I1/COX IV, cytochrome c oxidase subunit 4I1; CsA, cyclosporine A; ED50, 50% effective dose; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HPLC, high-performance liquid chromatography; JC-1, tetraethylbenz-imidazolylcarbocyanine iodide; LC3, microtubule-associated protein 1 light chain3; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LDH, lactate dehydrogenase; l-dopa, 3, 4-dihydroxyphenyl-l-alanine; MAPK8/JNK1, mitogen-activated protein kinase 8; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mRFP, monomeric red fluorescent protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFE2L2/NRF2, nuclear factor, erythroid derived 2, like 2; PD, Parkinson disease; PLG, piperlongumine; pNA, p-nitroanilide; PI, propidium iodide; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PTX, paclitaxel; Rap, rapamycin; SQSTM1/p62, sequestosome 1; TH, tyrosine hydroxylase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WIPI2, WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1, zinc finger, FYVE domain containing 1.

Improved neuroprotective effect of resveratrol nanoparticles as evinced by abrogation of rotenone-induced behavioral deficits and oxidative and mitochondrial dysfunctions in rat model of Parkinson's disease.

The objective of the present study was to evaluate the protective effect of resveratrol nanoparticles (NRSV) against rotenone-induced neurodegeneration in rats. NRSV were prepared by temperature-controlled antisolvent precipitation method and characterized for its particle size, shape, and dissolution properties. Moreover, NRSV effects compared with the free resveratrol (RSV). Animals were divided into four groups: (I) control, (II) rotenone (2mg/kg s.c.), (III) RSV (40mg/kg, p.o.) + rotenone, and (IV) NRSV (40mg/kg, p.o.) + rotenone. Animals received treatments 30min before rotenone administration for a period of 35days. Behavioral quantifications were done using rota rod test and rearing behavior after 24h of last dose. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH), and catalase), and complex-I activity. In addition, histopathological studies were also performed. Our results showed that chronic rotenone treatment causes motor deficits, decreased rearing behavior, mitochondrial dysfunction, and oxidative stress. Furthermore, histological analysis demonstrated neuronal degeneration in rotenone-treated rats. An important finding of the present study was NRSV showed comparatively better efficacy than the RSV treatment in attenuating the rotenone-induced Parkinson's like behavioral alterations, biochemical and histological changes, oxidative stress, and mitochondrial dysfunction in rats.

Minocycline diminishes the rotenone induced neurotoxicity and glial activation via suppression of apoptosis, nitrite levels and oxidative stress

The study was conducted to evaluate the effect of minocycline against pesticide rotenone induced adverse effects in different rat brain regions. Assessment of oxidative stress, nitrite levels, degenerating neurons and level of cleaved caspase-3 was done in frontal cortex, mid brain, hippocampus and striatum regions of rat brain. In addition the expression profile of neuronal (MAP2), astrocytes (GFAP) and microglia (cd11b) markers was done after treatments. Rotenone induced DNA fragmentation was also assessed in all studied rat brain regions by utilizing comet assay. Rotenone administration caused significantly decreased level of glutathione along with increased level of nitrite and lipid peroxidation. Significant oxidative and nitrosative stress was also observed after rotenone administration which was considerably inhibited in minocycline treated rats in time dependent manner. Fluorojade staining and levels of cleaved caspase 3 showed the degeneration of neurons and apoptosis respectively in studied rat brain regions which were further inhibited with minocycline treatment. Rotenone administration caused significantly increased reactivity of astrocytes, microglia and altered neuronal morphology in rat brain regions which was also partially restored with minocycline treatment. In conclusion, present study showed that minocycline treatment attenuated the rotenone induced oxidative stress, nitrite level, degeneration of neurons, augmented glial reactivity and apoptosis.

Neuroprotection by misoprostol against rotenone-induced neurotoxicity in rat brain

Objective: To investigate the effect of the prostaglandin E1 analogue misoprostol on oxidative stress and neurodegeration caused by subcutaneous rotenone administration in rats. Methods: Rotenone was administered in a dose of 1.5 mg/kg every other day for 2 weeks. Starting from the 1st day of rotenone injection, rats were subcutaneously treated with misoprostol at doses of 10, 100 or 1 000 μ g/kg. Rats were evaluated for brain lipid peroxidation (malondialdehyde: MDA), reduced glutathione (GSH), nitric oxide (NO) levels, and paraoxonase-1 (PON-1) activity. The concentrations of the anti-apoptotic protein B cell/lymphoma-2 (Bcl-2) were determined in the striatum. Histopathologic examination and the expression of inducible nitric oxide synthase (iNOS) in the cerebral cortex and striatum were also performed. Results: Compared with the vehicle-treated group, rotenone caused a significant increase in brain lipid proxidation (MDA) by 61% (P

Myricetin attenuates neurodegeneration and cognitive impairment in Parkinsonism.

Parkinson's disease (PD) is a progressive neurodegenerative disease due to dopaminergic neuron degeneration. It mostly affects the aged population, leads to memory decline and loss of motor coordination. The present study investigates the neuroprotective role of myricetin a flavonol isolated from the brown seaweed Turbinaria ornata in rotenone induced Drosophila model of PD. Rotenone administration led to dopaminergic neuronal degeneration, dopamine depletion, impaired muscular coordination, gait disturbances, memory decline oxidative stress and apoptosis. Ingestion of myricetin by Drosophila significantly prevented rotenone induced neuronal degeneration. These results confirm that myricetin exerts neuroprotective effect in experimental PD.

Immunomorphological Changes in the Olfactory Bulbs of Rats after Intranasal Administration of Rotenone.

Changes in the structure of the olfactory bulbs after long-term intranasal administration of pesticide rotenone, a classical inductor of parkinsonism, to rats were studied by the methods of immunomorphology. In rats intranasally receiving rotenone in a dose of 2.5 mg/kg every other day over 2 weeks, a decrease in the density of dopaminergic neurons and the area of astrocyte processes in the olfactory bulbs, activation of microglia in the glomerular layer, and enhanced α-synuclein phosphorylation and its accumulation in the bodies of mitral layer neurons were observed. The observed changes agree with the hypothesis on pathological α-synuclein transport via the olfactory route in Parkinson's disease and confirm relevance of the rotenone model of Parkinson's disease for studies of the pathological accumulation of α-synuclein.

Evolution of anti-parkinsonian activity of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol in various in vivo models

It has been found recently that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Diol) demonstrates high antiparkinsonian activity in some animal models. We carried out an extended study of the antiparkinsonian activity of Diol in a set of relevant animal models. Diol (20mg/kg) exhibited an anticataleptogenic effect in the haloperidol-induced catalepsy model and restored motor activity in animals in the reserpine-induced model of oligokinesia. The ability of Diol singly administered before MPTP injection to reduce rigidity comparable to that of activity of L-DOPA (100mg/kg) was found using the model of Parkinsonian syndrome (PS) induced by single injection of MPTP (30mg/kg) to C57BL/6 mice. In the model of PS induced by subchronic administration of MPTP (4 × 20mg/kg), Diol at a dose of 20mg/kg reduced rigidity with effectiveness comparable to that of L-DOPA, while being superior to L-DOPA in terms of its effect on motor activity. It was found using the model of PS induced by systemic administration of rotenone that subchronic daily oral administration of Diol prior to rotenone injection reduced severity of PS in rats. Assessment of the effects of chronic administration of Diol (20mg/kg) and L-DOPA to animals with 6-OHDA-induced PS showed that administration of Diol alleviated the symptoms of sensorimotor deficit in right limbs in rats. Thus, the potent antiparkinsonian activity of Diol was demonstrated in all the used rodent models experiments. Diol (20mg/kg) is as effective as the comparator agent L-DOPA administered at doses of 50–100mg/kg.

Treatment of rotenone induced neurodegeneration by taurine and hesperidin

Taurine (2-aminoethane sulphonic acid) is a sulphonic acid which is derived from cysteine and is widely distributed in animal tissues. It is one of the most abundant amino acid in mammals and plays several crucial roles including modulation of calcium signaling, osmoregulation and membrane stabilization. Hesperidin occurs in the cells in crystalline, feather-like aggregates or sphaerocrytalline masses and it exhibits pharmacological and biological properties such as anti-inflammatory, anticarcinogenic, inhibit bone loss, lowering of lipid, hypoglycaemic and antioxidant activities. The current study was performed to evaluate the effect of taurine and hesperidin on neurodegeneration resulted from rotenone administration by a dose of 1.5 mg/kg b.wt three times per week for two months. Also we summarize recent findings emphasizing the role of catecholamines neurotransmitters, Tyrosine hydroxylase and oxidative stress in neurodegenerative disease model. These rats received taurine and hesperidin through gastric intubation daily for one month after rotenone administration. The results revealed that taurine and hesperidin treatment significantly ameliorated the decreased levels of the catecholamines neurotransmitters and Tyrosine hydroxylase which were decreased as after rotenone injection. Moreover, taurine and hesperidin treatment ameliorated lipid peroxidation and catalase levels.

Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosis

Previous studies have examined rotenone toxicity on the human central nervous system, especially in the pathogenesis of Parkinson’s disease, but few have investigated the effects of rotenone on the kidney. Here, rotenone-induced nephrotoxicity was evaluated by determining morphological, biochemical, oxidative stress-related, and apoptotic factor alterations in rat renal tissue. Morphological and biochemical analyzes showed that rotenone administration to rats damaged renal tissue. Western blot results revealed that rotenone-induced oxidative damage, causing overproduction of glutathione, malonaldehyde, and reactive oxygen species (ROS), and inhibiting superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Rotenone also decreased the mitochondrial membrane potential and increased voltage-dependent anion channel (VDAC), caspase-3, and caspase-9 protein levels, indicating an association of apoptosis with renal damage. Our results suggest that glutathione, malonaldehyde, and ROS may be signals of rotenone-induced oxidative damage, and that the mitochondrial pathway plays a key role in apoptosis of renal cells following rotenone administration.

Neuroprotective effect of resveratrol on rotenone-treated C57BL/6 mice.

The aim of the present study was to investigate whether resveratrol could reduce nigral iron levels to prevent the degeneration of dopaminergic neurons in the substantia nigra (SN) of C57BL/6 mice induced by rotenone. Parkinson's disease (PD) is an age-related neurodegenerative disorder; elevated iron levels in the SN participate in neuronal death in PD. Resveratrol is a kind of polyphenolic compounds and possess antioxidant, anticancer, and anti-inflammatory biological functions. Although many research groups have investigated the neuroprotective effects of resveratrol against PD, the precise mechanisms underlying its beneficial effects on dopaminergic neuron are poorly defined. In this study, rotenone-treated mice were used to examine neuroprotective roles of resveratrol in PD. Sixty-four adult C57BL/6 mice were divided into four groups: vehicle control mice, rotenone mice, resveratrol-treated rotenone mice, resveratrol mice. In the present study, we found that chronic administration of rotenone significantly induced motor coordination impairment and increased iron levels and dopaminergic neuron loss in SN in mice. Resveratrol administration significantly protected mice from rotenone-induced motor coordination impairment, elevated iron levels, and dopaminergic neuronal loss. Our results show that resveratrol can elicit neuroprotective effects on rotenone-induced parkinsonism through reducing nigral iron levels.

Rotenone decreases ischemia-induced injury by inhibiting mitochondrial permeability transition in mature brains

The mitochondrial permeability transition pore (mPTP) is thought to be implicated in brain ischemia-induced cell death. Here we sought to determine whether complex I (CI) of the mitochondrial electron transfer system may be involved in regulation of mPTP opening during ischemia and whether a specific inhibitor of this complex – rotenone can protect against ischemia-induced cell death in an experimental model of total ischemia in adult rat brains. Anesthetized Wistar rats were administered a single injection of rotenone (0.01mg/kg) to the tail vein and brains were removed and subjected to 120min ischemia. We found that intravenous injection of rotenone 20min before ischemia increased resistance to Ca2+-induced mPTP opening and decreased production of reactive oxygen species (ROS) in mitochondria isolated from ischemia-damaged cortex and cerebellum. Rotenone administration before ischemia decreased infarct size in both brain regions (cortex and cerebellum). Rotenone added directly to normal, non-ischemic cortical or cerebellar mitochondria increased their resistance to Ca2+-induced mPTP opening at concentration which fully inhibited NAD-dependent mitochondrial respiration. Our data demonstrate that rotenone used intravenously may be protective against acute brain ischemia-induced injuries by inhibition of mPTP opening and ROS production. These findings suggest that CI of mitochondrial electron transfer system plays a role in mPTP regulation during cerebral ischemia in mature brains and that agents acting on CI activity may be clinically useful for stroke therapy.

Gut–brain and brain–gut axis in Parkinson's disease models: Effects of a uridine and fish oil diet

Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The ‘dual-hit’ hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this ‘dual-hit hypothesis’ and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models. Mice were given rotenone either orally or by an injection in the striatum. Dietary interventions were started 1 week before rotenone exposures. We found that (1) both oral and intrastriatal administration of rotenone induced similar PD-like motor deficits, dopaminergic cell loss, delayed intestinal transit, inflammation, and alpha-synuclein accumulation in the colon; (2) the uridine and DHA containing diet prevented rotenone-induced motor and GI dysfunctions in both models. The models suggest possible bidirectional communication between the gut and the brain for the genesis of PD-like phenotype and pathology. The dietary intervention may provide benefits in the prevention of motor and non-motor symptoms in PD.

Rotenone impairs hippocampal neuronal activity in a rat model of Parkinson’s disease

Parkinson’s disease (PD) is the most common neurodegenerative disease of unknown etiology and characterized by motor symptoms of tremor, rigidity, bradykinesia, and postural instability. Interactions between the dopaminergic systems and the hippocampus in synaptic plasticity and behavior are found. The rotenone-induced animal model is commonly used in research studies involved in PD. Administration of rotenone causes alterations of electrical neuronal activity. Rotenone (2.5 mg/kg/day) was administered intraperitoneally for 21 days to adult rats, and rotenone effects on rearing activity and electrophysiology were examined. Dose-dependent reduction of evoked neural activity and a reduction in firing strength were found in the hippocampus. Behaviorally, Rotenone rats showed a more consistent decrease in rearing across the 3 weeks, compared with animals in the control group. Thus, rotenone causes changes in hippocampal electrical activity and behavioral changes.