Hemiparkinsonian Model Research Articles

β-Caryophyllene decreases neuroinflammation and exerts neuroprotection of dopaminergic neurons in a model of hemiparkinsonism through inhibition of the NLRP3 inflammasome

β-Caryophyllene decreases neuroinflammation and exerts neuroprotection of dopaminergic neurons in a model of hemiparkinsonism through inhibition of the NLRP3 inflammasome

Oral Administration of Lactobacillus Inhibits the Permeability of Blood-Brain and Gut Barriers in a Parkinsonism Model.

It has recently been shown that the administration of probiotics can modulate the microbiota-gut-brain axis and may have favorable effects in models of Parkinson's disease. In this study, we used a hemiparkinsonism model induced by the neurotoxin 6-OHDA to evaluate the efficacy of the administration of a four-week administration of a mixture containing the microorganisms Lactobacillus fermentum LH01, Lactobacillus reuteri LH03, and Lactobacillus plantarum LH05. The hemiparkinsonism model induced an increase in rotations in the apomorphine test, along with a decrease in the latency time to fall in the rotarod test on days 14 and 21 after surgery, respectively. The administration of probiotics was sufficient to improve this condition. The model also showed a decrease in tyrosine hydroxylase immunoreactivity in the striatum and the number of labeled cells in the substantia nigra, both of which were counteracted by the administration of probiotics. The permeability of the blood-brain barrier was increased in the model, but this effect was reversed by the probiotics for both brain regions. The gut barrier was permeated with the model, and this effect was reversed and dropped to lower levels than the control group after the administration of probiotics. Finally, lipid peroxidation showed a pattern of differences similar to that of permeabilities. The inhibition of the permeability of the blood-brain and gut barriers mediated by the administration of probiotics will likely provide protection by downregulating oxidative stress, thus affecting the rotarod test performance.

β-Caryophyllene decreases neuroinflammation and exerts neuroprotection of dopaminergic neurons in a model of hemiparkinsonism through inhibition of the NLRP3 inflammasome

IntroductionParkinson's disease represents a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the Substantia Nigra pars compacta (SNpc), resulting in diminished dopamine levels in the striatum (STR) and chronic neuroinflammation. Recent investigations have proposed the neuroprotective potential of the endocannabinoid system in neurodegenerative disorders. β-caryophyllene (BCP) is recognized for its antioxidant and anti-inflammatory properties, attributed to its activation of the type 2 cannabinoid receptor. This study aimed to assess the neuroprotective impact of BCP on dopaminergic neurons, with a particular focus on inhibiting the NLRP3 inflammasome. MethodsA model of hemiparkinsonism, induced by 6-hydroxydopamine (6-OHDA), served as the experimental framework. Motor function was evaluated using the cylinder test, and inflammasome inhibition was determined by assessing the expression of NLRP3, caspase-1, and the pro-inflammatory cytokine IL-1β in both the SNpc and STR through ELISA analysis. Furthermore, the evaluation of oxidative stress was facilitated by quantifying malondialdehyde (MDA) levels in the same regions. ResultsBCP treatment demonstrated significant improvements in motor dysfunction, as assessed by the cylinder test (p=0.0011) and exhibited a neuroprotective effect on dopaminergic neurons within the SNpc (p=0.0017), as well as nerve fibers in the STR (p=0.0399). In terms of its ability to inhibit the inflammasome, BCP led to decreased expression levels of NLRP3 (p=0.0401 in STR and p = 0.0139 in SNpc), caspase-1 (p=0.0004 in STR), and MDA (p=0.0085 in STR and p=0.0414 in SNpc). ConclusionThese results point to BCP's potential in mitigating the motor deficit, inhibiting NLRP3 inflammasome activation, and attenuating lipid peroxidation induced by 6-OHDA.

In the Rat Midbrain, SG2NA and DJ-1 have Common Interactome, Including Mitochondrial Electron Transporters that are Comodulated Under Oxidative Stress.

Scaffold proteins Striatin and SG2NA assemble kinases and phosphatases into the signalling complexes called STRIPAK. Dysfunctional STRIPAKs cause cancer, cerebral cavernous malformations, etc. DJ-1, a sensor for oxidative stress, has long been associated with the Parkinson's disease, cancer, and immune disorders. SG2NA interacts with DJ-1 and Akt providing neuroprotection under oxidative stress. To dissect the role of SG2NA and DJ-1 in neuronal pathobiology, rat midbrain extracts were immunoprecipitated with SG2NA and sixty-three interacting proteins were identified. BN-PAGE followed by the LC-MS/MS showed 1030 comigrating proteins as the potential constituents of the multimeric complexes formed by SG2NA. Forty-three proteins were common between those identified by co-immunoprecipitation and the BN-PAGE. Co-immunoprecipitation with DJ-1 identified 179 interacting partners, of which forty-one also interact with SG2NA. Among those forty-one proteins immunoprecipitated with both SG2NA and DJ-1, thirty-nine comigrated with SG2NA in the BN-PAGE, and thus are bonafide constituents of the supramolecular assemblies comprising both DJ-1 and SG2NA. Among those thirty-nine proteins, seven are involved in mitochondrial oxidative phosphorylation. In rotenone-treated rats having Parkinson's like symptoms, the levels of both SG2NA and DJ-1 increased in the mitochondria; and the association of SG2NA with the electron transport complexes enhanced. In the hemi-Parkinson's model, where the rats were injected with 6-OHDA into the midbrain, the occupancy of SG2NA and DJ-1 in the mitochondrial complexes also increased. Our study thus reveals a new family of potential STRIPAK assemblies involving both SG2NA and DJ-1, with key roles in protecting midbrain from the oxidative stress.

Striatal serotonin transporter gain-of-function in L-DOPA-treated, hemi-parkinsonian rats

L-DOPA is the standard treatment for Parkinson’s disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex interaction between the remaining dopamine (DA) system and the semi-homologous serotonin (5-HT) system. Since serotonin transporters (SERT) have some affinity for DA uptake, they may serve as a functional compensatory mechanism when DA transporters (DAT) are scant. DAT and SERT’s functional contributions in the dyskinetic brain have not been well delineated. The current investigation sought to determine how DA depletion and L-DOPA treatment affect DAT and SERT transcriptional processes, translational processes, and functional DA uptake in the 6-hydroxydopamine-lesioned hemi-parkinsonian rat. Rats were counterbalanced for motor impairment into equally lesioned treatment groups then given daily L-DOPA (0 or 6 mg/kg) for 2 weeks. At the end of treatment, the substantia nigra was processed for tyrosine hydroxylase (TH) and DAT gene expression and dorsal raphe was processed for SERT gene expression. The striatum was processed for synaptosomal DAT and SERT protein expression and ex vivo DA uptake. Nigrostriatal DA loss severely reduced DAT mRNA and protein expression in the striatum with minimal changes in SERT. L-DOPA treatment, while not significantly affecting DAT or SERT alone, did increase striatal SERT:DAT protein ratios. Using ex vivo microdialysis, L-DOPA treatment increased DA uptake via SERT when DAT was depleted. Overall, these results suggest that DA loss and L-DOPA treatment uniquely alter DAT and SERT, revealing implications for monoamine transporters as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.

The effects of betulinic acid chronic administration on the motor, non-motor behaviors, and globus pallidus local field potential power in a rat model of hemiparkinsonism.

Parkinson's disease (PD) is a neurodegenerative disorder involving the central nervous system associated with motor and non-motor impairments. Betulinic acid (BA) is a natural substance considered an antioxidative agent. This study aimed to investigate the therapeutic potential of BA on motor dysfunctions and globus pallidus (GP) local EEG power in a 6-hydroxydopamine (6-OHDA)-induced rat model of hemiparkinsonism. Adult Wistar rats were categorized into different groups, containing; Sham, PD, and treated groups including different doses of BA (0.5, 5, and 10 mg/kg, IP), and L-dopa (20 mg/kg, PO, as positive control). The lesion was induced in the right medial forebrain bundle by injection of 6-OHDA (20 µg/kg). The treatment was begun just after the approved rotational test induced by apomorphine, 14 days after 6-OHDA administration. Motor behaviors such as catalepsy and stride-length and non-motor responses, including GP local EEG, were then assessed. Also, the levels of GSH, catalase, and concentration of dopamine in the brain tissue were measured. Treatment of hemiparkinsonian rats with BA significantly improved catalepsy and stride-length (P<0.001 and P<0.01, respectively) and GP frequency bands' powers (P<0.001). Moreover, the activities of GSH (P<0.001), catalase (P<0.001), and the concentration of dopamine (P<0.001) in the brain were increased. Current results proved the potent ability of BA to scavenge free radicals and to remove oxidative agents in the brain tissue. This natural product could be considered a possible therapeutic compound for motor and non-motor disorders in PD.

Spatial clustering of substantia nigra astrocytes analyzed in rotenone model of hemiparkinsonism

This paper addresses spatial aspects of reactive astrogliosis in the substantia nigra pars compacta (SNc) of the rat brain observed 40 and 70 days after the intracerebral 12 µg rotenone infusion. The infusion was shown to cause a marked increase in astrocyte density at both analyzed time points. Minimal spanning tree (MST) analysis was applied to analyze spatial patterns formed by nigral astrocytes. Spatial clusters of these cells, identified as disjoint MST subgraphs, were more numerous in the infused SNc tissue as compared with the control one. Size and density of clusters were significantly different between the infused and control areas 40 and 70 days after the infusion. In conclusion, the data suggests that rotenone-related astrogliosis in the substantia nigra includes changes in spatial patterns of astrocytes as well as transient spatial clustering of these cells.

Hippocampal and Reticulo-Thalamic Parvalbumin Interneurons and Synaptic Re-Organization during Sleep Disorders in the Rat Models of Parkinson's Disease Neuropathology.

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson’s disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.

Knock-Down of GPR88 in the Dorsal Striatum Alters the Response of Medium Spiny Neurons to the Loss of Dopamine Input and L-3-4-Dyhydroxyphenylalanine.

The effects of L-3-4-dyhydroxyphenylalanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson’s disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search for new treatments. The orphan G protein-coupled receptor 88 (Gpr88) represents a potential new target, as it is highly and almost exclusively expressed in the projecting gamma-Aminobutyric Acid-ergic (GABAergic) medium spiny neurons of the striatum, is implicated in motor activity, and is downregulated by 6-hydroxydopamine (6-OHDA) lesions, an effect that is reversed by L-DOPA. Thus, to evaluate Gpr88 as a potential target for the management of PD and L-DOPA–induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemiparkinsonism. Then, we investigated the effects of the KD-Gpr88 in the DA-deprived dorsal striatum on circling behavior and LID as well as on specific markers of striatal neuron activity. The KD-Gpr88 reduced the acute amphetamine-induced and increased L-DOPA–induced turning behavior. Moreover, it normalized the upregulated expression of striatal Gad67 and proenkephalin provoked by the 6-OHDA lesion. Finally, despite promoting ΔFosB accumulation, the KD-Gpr88 was associated neither with the upregulation of prodynorphin, which is causally linked to the severity of LID, nor with the aggravation of LID following chronic L-DOPA treatment in 6-OHDA–lesioned rats. These results thus justify further evaluation of Gpr88 as a potentially novel target for the management of PD as an alternative to L-DOPA therapy.

Differential Changes in the Lateralized Activity of Identified Projection Neurons of Motor Cortex in Hemiparkinsonian Rats.

In the parkinsonian state, the motor cortex and basal ganglia (BG) undergo dynamic remodeling of movement representation. One such change is the loss of the normal contralateral lateralized activity pattern. The increase in the number of movement-related neurons responding to ipsilateral or bilateral limb movements may cause motor problems, including impaired balance, reduced bimanual coordination, and abnormal mirror movements. However, it remains unknown how individual types of motor cortical neurons organize this reconstruction. To explore the effect of dopamine depletion on lateralized activity in the parkinsonian state, we used a partial hemiparkinsonian model [6-hydroxydopamine (6-OHDA) lesion] in Long–Evans rats performing unilateral movements in a right–left pedal task, while recording from primary (M1) and secondary motor cortex (M2). The lesion decreased contralateral preferred activity in both M1 and M2. In addition, this change differed among identified intratelencephalic (IT) and pyramidal tract (PT) cortical projection neurons, depending on the cortical area. We detected a decrease in lateralized activity only in PT neurons in M1, whereas in M2, this change was observed in IT neurons, with no change in the PT population. Our results suggest a differential effect of dopamine depletion in the lateralized activity of the motor cortex, and suggest possible compensatory changes in the contralateral hemisphere.

Video-based assessments of the hind limb stepping in a mouse model of hemi-parkinsonism

Unilateral injection of 6-hydroxydopamine (6-OHDA) is commonly used to generate a rodent model of Parkinson’s disease (PD). Although motor deficits of the lower extremities represent one of the major clinical symptoms in PD patients, validated tests for assessing motor impairments of the hind limb in 6-OHDA mice are currently unavailable. We here report the video-based assessments of the asymmetric use of hind limbs in 6-OHDA mice. A significantly decreased number of spontaneous hind limb stepping was observed in the contralateral-to-lesioned side, and was dose dependently reversed by levodopa, suggesting that it could be utilized for screening PD therapeutics.

Effects of subthalamic deep brain stimulation on striatal metabolic connectivity in a rat hemiparkinsonian model.

ABSTRACTDeep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular. We used ipsilesional STN stimulation in a hemiparkinsonian rat model in combination with [18F]FDOPA-PET, [18F]FDG-PET and metabolic connectivity analysis. STN-DBS reversed ipsilesional hypometabolism and contralesional hypermetabolism in hemiparkinsonian rats by increasing metabolic activity in the ipsilesional ventrolateral striatum and by decreasing it in the contralesional hippocampus and brainstem. Other STN-DBS effects were subject to the magnitude of dopaminergic lesion severity measured with [18F]FDOPA-PET, e.g. activation of the infralimbic cortex was negatively correlated to lesion severity. Connectivity analysis revealed that, in healthy control animals, left and right striatum formed a bilateral functional unit connected by shared cortical afferents, which was less pronounced in hemiparkinsonian rats. The healthy striatum was metabolically connected to the ipsilesional substantia nigra in hemiparkinsonian rats only (OFF condition). STN-DBS (ON condition) established a new functional striatal network, in which interhemispheric striatal connectivity was strengthened, and both the dopamine-depleted and the healthy striatum were functionally connected to the healthy substantia nigra. We conclude that both unilateral dopamine depletion and STN-DBS affect the whole brain and alter complex interhemispheric networks.

Rebamipide Mitigates Impairments in Mitochondrial Function and Bioenergetics with α-Synuclein Pathology in 6-OHDA-Induced Hemiparkinson's Model in Rats.

Parkinson's disease (PD) is one of the widely reported neurodegenerative disorders affecting more than ten million people worldwide. Due to therapeutic limitations and several adverse effects associated with currently used drugs, it is crucial to search for safe and effective options for treatment of PD. Oxidative stress, mitochondrial dysfunction, α-synuclein oligomeric aggregates, and glucocerebrosidase (GCase) deficiency are involved in PD pathogenesis. Rebamipide, an anti-ulcer drug, is a proven free-radical scavenger and antioxidant. The drug has shown neuroprotective effects in cultured SH-SY5Y cells. Therefore, we investigated the pharmacological effect of rebamipide in 6-hydroxydopamine (6-OHDA)-induced experimental PD model. Rebamipide was given to adult male albino rats of Charles-Foster strain in 20, 40, and 80mg/kg (R-20, R-40, and R-80) oral dose twice daily for 24days (day 4 to day 27) after 6-OHDA intrastriatal injection. The drug inhibited 6-OHDA-induced motor deficits and nigral α-synuclein aggregates in dose-dependent manner. R-40 and R-80 dose dependently increased striatal mitochondrial complex I, II, IV, and V activities; mitochondrial bioenergetics; and nigral GCase activity. 6-OHDA-induced lipid peroxidation was decreased. Highest dose (R-80) also decreased apoptotic proteins and upregulated striatal dopamine concentration in 6-OHDA-induced hemiparkinson's rat model. Therefore, the anti-PD effect of rebamipide may involve stabilization of mitochondrial bioenergetics, enhancement of GCase enzymatic activity as well as decreased oxidative stress with α-synuclein pathology, and apoptosis in 6-OHDA-induced hemiparkinson's rat model. Hence, preclinical evidence indicates rebamipide to be a potential drug for management of PD.

Protective and therapeutic activity of honokiol in reversing motor deficits and neuronal degeneration in the mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive and profound movement disorder resulting from neurodegeneration in the nigrostriatal dopaminergic system, but current treatment neither cures nor stops PD from advancing. Based on the ability to suppress oxidative stress, excitotoxicity, and neuroinflammation, the potential of honokiol as a novel neuroprotective agent for PD treatment was determined. The hemi-parkinsonian model was used to investigate the protective and therapeutic effects of honokiol on motor dysfunctions and dopaminergic neurodegeneration in mice, with a single unilateral striatal injection of 6-hydroxydopamine (6-OHDA). One day after 6-OHDA-induced lesion, the mice exhibited spontaneous ipsilateral turning, motor imbalance, and incoordination which were mild with a single administration of honokiol prior to 6-OHDA injection. Thereafter, honokiol was continually applied daily for 14 days, which ameliorated apomorphine-induced contralateral rotation and reduced the loss of tyrosine hydroxylase-immunoreactive (TH-ir) fibers in the lesioned striatum. In addition, honokiol posttreatment, beginning on day 8 after 6-OHDA lesion, for 14 days efficiently rescued motor deficits and recovered the TH-ir neuronal loss in both the lesioned striatum and the ipsilateral substantia nigra. The 6-OHDA-induced increases in nigrostriatal expression of inducible nitric oxide synthase (iNOS) and decreases in that of nNOS were also reversed by honokiol posttreatment. These findings revealed that honokiol has both protective and therapeutic effects on motor impairments and dopaminergic progressive damage, at least in part through modulation of NOS signaling, in 6-OHDA-lesioned mice. Honokiol may represent a potential therapeutic candidate for the management of motor symptoms and neurodegeneration in PD.

Real-time simultaneous recording of electrophysiological activities and dopamine overflow in the deep brain nuclei of a non-human primate with Parkinson\u2019s disease using nano-based microelectrode arrays

Parkinson’s disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons. The precise mechanisms are still unknown. Since the neuronal communications are inherently electrical and chemical in nature, dual-mode detection of PD-related neuroelectrical and neurochemical information is essential for PD research. Subthalamic nucleus (STN) high-frequency stimulation (HFS) can improve most symptoms of PD patients and decrease the dosage of antiparkinsonian drugs. The mechanism of STN-HFS for PD still remains elusive. In this study, a silicon-based dual-mode microelectrode array (MEA) probe was designed and fabricated, and systematic dual-mode detection methods were established. The recording sites were modified using Pt nanoparticles and Nafion to improve the signal-to-noise (SNR) ratio. To evaluate its applicability to PD research, in vivo electrophysiological and electrochemical detection was performed in normal and hemiparkinsonian models, respectively. Through comparison of the dual-mode signals, we demonstrated the following in a PD monkey: (1) the maximum dopamine concentration in the striatum decreased by 90%; (2) the spike firing frequency increased significantly, especially in the region of the cortex; (3) the spectrogram analysis showed that much power existed in the 0–10 Hz frequency band; and (4) following repeated subthalamic nucleus high-frequency stimulation trials, the level of DA in the striatum increased by 16.5 μM, which led to a better elucidation of the mechanism of HFS. The dual-mode MEA probe was demonstrated to be an effective tool for the study of neurological disorders.

Intrastriatally injected botulinum neurotoxin-A differently effects cholinergic and dopaminergic fibers in C57BL/6 mice

Unilateral intrastriatal BoNT-A injection abolished apomorphine-induced rotational behavior in a rat model of hemiparkinsonism (hemi-PD) up to 6months. It was hypothesized that the beneficial effect of botulinum neurotoxin-A (BoNT-A) grounded on the reduction of the Parkinson’s diseases (PD) associated striatal hypercholinism. Intrastriatal injection of BoNT-A was not cytotoxic in rat brain, but neuronal fiber swellings in the BoNT-A infiltrated striata appeared and named BoNT-A-induced varicosities (BiVs). In the rat BiVs were immunoreactive (ir) either for choline acetyltransferase (ChAT) or tyrosine hydroxylase (TH). In the present study the structural effect of unilateral intrastriatal BoNT-A injection in the naïve mouse brain was analyzed to extend possible therapeutic BoNT-A applications to genetical Parkinsonian strains.We investigated the effect of a single dose of 25pg BoNT-A injected into the right caudate-putamen (CPu) for up to 9months, and of increasing doses up to 200pg on striatal volume, number of ChAT-ir interneurons, and numeric density and volume of the ChAT-ir BiVs in comparison to the uninjected hemisphere.Intrastriatal BoNT-A injection did not alter the number of ChAT-ir interneurons irrespective of survival time and dosage tested. However, the numeric density of the ChAT-ir BiVs at a dose of 25pg increased from 1 to 3months after BoNT-A, followed by a time dependent decrease. In parallel, with increasing BoNT-A survival time, the mean BiV volume increased as the number of small BiVs decreased. Interestingly, in contrast to rats we did not find TH-ir BiVs in BoNT-A injected mouse striatum.

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus.

Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.

Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns

BackgroundIn Parkinson’s disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model.ResultsWe found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation.ConclusionsOur results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

Carvacrol promotes neuroprotection in the mouse hemiparkinsonian model

Carvacrol is a monoterpene that has been linked to neuroprotection in several animal models of neurodegeneration, including ischemia, epilepsy and traumatic neuronal injury. In this study, we investigated the effects of carvacrol (i.p.) upon the neurodegeneration induced by 6-hydroxy-dopamine unilateral intrastriatal injections in mice. We have also used the cylinder test to assess the behavioral effects of carvacrol in that model of Parkinson’s disease, and immunoblots to evaluate the levels of caspase-3 and TRPM7, one of major targets of carvacrol. Behavioral testing revealed that carvacrol largely reduced the asymmetrical use of the forelimbs induced by unilateral 6-hydroxy-dopamine. Carvacrol dramatically reduced the loss of tyrosine hydroxylase immunostaining both in the substantia nigra and in the striatum that are typical of the model. Immunoblots for tyrosine hydroxylase confirmed this effect. Caspase-3 levels were very high after toxin injections, but carvacrol appeared to reduce them to control levels. Finally, TRPM7, observed by immunoblots, increased after 6-hydroxy-dopamine, suggesting the involvement of this cation channel in the ensuing neurodegenerative process. The present data suggest that carvacrol promotes a marked neuroprotection in the 6-hydroxy-dopamine model of Parkinson’s disease, possibly by its non-specific blocking effect upon TRPM7 channels.

Impact of the Chronic Omega-3 Fatty Acids Supplementation in Hemiparkinsonism Model Induced by 6-Hydroxydopamine in Rats.

Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In this study, the protective effect of ω-3 PUFA administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFA (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acid levels on the striatum from hemiparkinsonian rats, followed by reduction in the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, this study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action.