Rat Model Of Parkinson's Disease Research Articles

Vortioxetine ameliorates motor and cognitive impairments in the rotenone-induced Parkinson's disease via targeting TLR-2 mediated neuroinflammation

Parkinson's disease (PD) is characterized by motor and non-motor symptoms associated with dopaminergic and non-dopaminergic injury. Vortioxetine is a multimodal serotonergic antidepressant with potential procognitive effects. This study aimed to explore the effects of vortioxetine on motor functions, spatial learning and memory, and depression-like behavior in the rotenone-induced rat model of PD. Male Sprague-Dawley rats were daily administered with the rotenone (2 mg kg−1, s.c.) and/or vortioxetine (10 mg kg−1, s.c.) for 28 days. Motor functions (rotarod, catalepsy, open-field), depression-like behaviors (sucrose preference test), anxiety (elevated plus maze), and spatial learning and memory abilities (novel object recognition and Morris water maze) were evaluated in behavioral tests. Then immunohistochemical, neurochemical, and biochemical analysis on specific brain areas were performed. Vortioxetine treatment markedly reduced rotenone-induced neurodegeneration, improved motor and cognitive dysfunction, decreased depression-like behaviors without affecting anxiety-like parameters. Vortioxetine also restored the impaired inflammatory response and affected neurotransmitter levels in brain tissues. Interestingly, vortioxetine was thought to trigger a sort of dysfunction in basal ganglia as evidenced by increased Toll-like receptor-2 (TLR-2) and decreased TH immunoreactivity only in substantia nigra tissue of PD rats compared to the control group. The present study indicates that vortioxetine has beneficial effects on motor dysfunction as well as cognitive impairment associated with neurodegeneration in the rotenone-induced PD model. Possible mechanisms underlying these beneficial effects cover TLR-2 inhibition and neurochemical restoration of vortioxetine.

Neuroprotective effects of curcumin on the cerebellum in a rotenone-induced Parkinson's Disease Model.

AimsParkinson'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.MethodsForty 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).ResultsCompared 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.ConclusionCurcumin 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.

Pharmacological Modulation of TRPM2 Channels via PARP Pathway Leads to Neuroprotection in MPTP-induced Parkinson's Disease in Sprague Dawley Rats.

Transient receptor potential melastatin-2 (TRPM2) channels are cation channels activated by oxidative stress and ADP-ribose (ADPR). Role of TRPM2 channels has been postulated in several neurological disorders, but, it has not been explored in animal models of Parkinson's disease (PD). Thus, the role of TRPM2 and its associated poly (ADPR) polymerase (PARP) signaling pathways were investigated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model using TRPM2 inhibitor, 2-aminoethyl diphenyl borinate (2-APB), and PARP inhibitor, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34). PD was induced by using a bilateral intranigral administration of MPTP in rats, and different parameters were evaluated. An increase in oxidative stress was observed, leading to locomotor and cognitive deficits in the PD rats. PD rats also showed an increased TRPM2 expression in the striatum and mid-brain accompanied by reduced expression of tyrosine hydroxylase (TH) in comparison to sham animals. Intraperitoneal administration of 2-APB and PJ-34 led to an improvement in the locomotor and cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and an increase in TH levels in the striatum and mid-brain. In addition, these pharmacological interventions also led to a decrease in the expression of TRPM2 in PD in the striatum and mid-brain. Our results provide a rationale for the development of potent pharmacological agents targeting the TRPM2-PARP pathway to provide therapeutic benefits for the treatment of neurological diseases like PD.

Hydrogen Sulfide Attenuates the Cognitive Dysfunction in Parkinson's Disease Rats via Promoting Hippocampal Microglia M2 Polarization by Enhancement of Hippocampal Warburg Effect.

Identification of innovative therapeutic targets for the treatment of cognitive impairment in Parkinson's disease (PD) is urgently needed. Hydrogen sulfide (H2S) plays an important role in cognitive function. Therefore, this work is aimed at investigating whether H2S attenuates the cognitive impairment in PD and the underlying mechanisms. In the rotenone- (ROT-) established PD rat model, NaHS (a donor of H2S) attenuated the cognitive impairment and promoted microglia polarization from M1 towards M2 in the hippocampus of PD rats. NaHS also dramatically upregulated the Warburg effect in the hippocampus of PD rats. 2-Deoxyglucose (2-DG, an inhibitor of the Warburg effect) abolished NaHS-upregulated Warburg effect in the hippocampus of PD rats. Moreover, the inhibited hippocampal Warburg effect by 2-DG abrogated H2S-excited the enhancement of hippocampal microglia M2 polarization and the improvement of cognitive function in ROT-exposed rats. Our data demonstrated that H2S inhibits the cognitive dysfunction in PD via promoting microglia M2 polarization by enhancement of hippocampal Warburg effect.

Testing efficacy of the nicotine protection of the substantia nigra pars compacta in a rat Parkinson disease model. Ultrastructure study

ABSTRACT Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with subsequent motor manifestations. This study aimed to assess the ameliorative effects of nicotine, in rotenone-induced PD rat model. Thirty adult male Albino Wistar rats were divided into three equal groups. Group I received an injection of normal saline. Group II received subcutaneous injection of rotenone at a dose of 1.5 mg/kg every other day. Group III received rotenone in the same previous dose and nicotine at a dose of 1.5 mg/kg daily. After 11 days of treatment, body weight (BW) and rat motor behavior were estimated. Specimens from the midbrain were processed for light and electron microscopy. The expression of tyrosine hydroxylase (TH), α-synuclein, and GFAP was examined. Serum levels of total antioxidant capacity (TAC) and malondialdehyde (MDA), and striatal levels of dopamine (DA) were analyzed. Group III revealed a significant improvement in BW and motor activity. Nicotine upregulated the expression of TH, downregulated the expression of α-synuclein and GFAP. The levels of MDA and TAC were improved but were still far from those of the control. Striatal DA levels increased. Nicotine activated the neurons and glial cells. The vascular endothelium, however, did not elicit improvement. Although nicotine ameliorated the loss of the dopaminergic neurons and motor deficit, it did not show improvement of vascular endothelium. It is still necessary to examine nicotin’s ability to maintain the dopaminergic neurons in a good functioning state.

Er-Bai-Tang decoction improved the movement disorders and neuronal injury in the Parkinson's disease model rats via decreasing p38 MAPK pathway and improving the composition of intestinal flora.

Our previous study showed that Er-Bai-Tang decoction (EBT) could effectively improve Parkinson's disease (PD) patients' quality of life, sleep, mood, and cognitive disorders, but the mechanism of EBT to treat PD was unclear. So, our study aimed to explore the mechanism of EBT to treat PD via p38 mitogen-activated protein kinases (MAPK) pathway and intestinal flora. In our study, the PD rat model was established by subcutaneously injecting 2 mg/kg/d rotenone solution, and 23.43 g/kgEBT was used to treat PD model rats. Behavioral test showed that EBT could reverse the motor impairment in the PD model rats. Hematoxylin and eosin result showed that EBT could reduce the cell necrosis in the SNpc area of the PD model rats. Western blotting and real time-polymerase chain reaction showed that EBT could decrease the p38 MAPK expression in the SNpc area of the PD model rats. 16s rRNA sequencing analysis showed that EBT could improve the composition of intestinal flora in the PD model rats. Rikenellaceae at family level and Alistipes and Allobaculum at the genus level were the key species in the PD development and EBT treatment to PD. KEGG showed that EBT might change the iron uptake in PD rats. EBT could improve the motor symptoms and neuronal injury in the PD model rat, and its mechanism may be related to decreasing p38 MAPK pathway and improving the composition of intestinal flora.

A mind in motion: Exercise improves cognitive flexibility, impulsivity and alters dopamine receptor gene expression in a Parkinsonian rat model

Cognitive impairment, particularly deficits in executive function (EF) is common in Parkinson's disease (PD) and may lead to dementia. There are currently no effective treatments for cognitive impairment. Work from our lab and others has shown that physical exercise may improve motor performance in PD but its role in cognitive function remains poorly eludicated. In this study in a rodent model of PD, we sought to examine whether exercise improves cognitive processing and flexibility, important features of EF. Rats received 6-hydroxydopamine lesions of the bilateral striatum (caudate-putamen, CPu), specifically the dorsomedial CPu, a brain region central to EF. Rats were exercised on motorized running wheels or horizontal treadmills for 6-12 weeks. EF-related behaviors including attention and processing, as well as flexibility (inhibition) were evaluated using either an operant 3-choice serial reaction time task (3-CSRT) with rule reversal (3-CSRT-R), or a T-maze task with reversal. Changes in striatal transcript expression of dopamine receptors (Drd1-4) and synaptic proteins (Synaptophysin, PSD-95) were separately examined following 4 weeks of exercise in a subset of rats. Exercise/Lesion rats showed a modest, yet significant improvement in processing-related response accuracy in the 3-CSRT-R and T-maze, as well as a significant improvement in cognitive flexibility as assessed by inhibitory aptitude in the 3-CSRT-R. By four weeks, exercise also elicited increased expression of Drd1, Drd3, Drd4, synaptophysin, and PSD-95 in the dorsomedial and dorsolateral CPu. Our results underscore the observation that exercise, in addition to improving motor function may benefit cognitive performance, specifically EF, and that early changes (by 4 weeks) in CPu dopamine modulation and synaptic connectivity may underlie these benefits.

Continuous SGB Inhibits Occurrence and Maintenance of Mechanical Hyperalgesia via Reducing Inflammatory Cytokines in Striatum and PAG of PD Nociception Rat Models.

To investigate the effect of stellate ganglion block (SGB) on nociception in Parkinson's disease (PD) rat models, and to clarify the associated mechanism. To generate PD nociception rat model 6-hydroxydopamine (6-OHDA) injection method was used. Paw withdrawal threshold (PWT) and paw retraction latency (PWL) was used to reflect mechanical stimulation and thermal stimulation, respectively, at pre-modeling and 1, 2, 3, 4 weeks post modeling. The preventive and therapeutic effects of SGB treatment on nociception were observed in Naive, Vehicle, and 6-OHDA group (model). Levels of IL-1β, IL-6, and TNF-α in striatum and periaqueductal gray (PAG) were detected with ELISA. 6-OHDA injection induced obvious reduction of bilateral PWT from 2 to 4 weeks post modeling, suggesting that PD nociception rat model was successfully established. Continuous SGB prevention inhibited mechanical hyperalgesia at 2, 3 and 4 weeks post modeling, and significantly reversed mechanical hyperalgesia at 3 and 4 weeks post modeling, compared with those of Saline group (p < 0.05). These results suggest that continuous SGB could effectively prevent and alleviate pain of PD rats. SGB treatment remarkably suppressed levels of inflammatory factors (IL-1 β, IL-6, and TNF-α) in striatum and PAG of PD rats compared with those of rats in Vehicle group (p < 0.05). Continuous SGB effectively inhibited and reversed mechanical hyperalgesia of PD nociception rats through inhibiting inflammatory response in striatum and PAG.

Effect of Varenicline on Detrusor Overactivity in Rat Model of Parkinson’s Disease Induced by Intranigral 6-Hydroxydopamine

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Bladder dysfunction is the common non-motor symptom of PD, most often presenting with detrusor overactivity (DO). Treatment of DO is currently limited, poorly tolerated and sometimes ineffective. Bladder responses are not only mediated by muscarinic cholinergic receptors (mAChR) but also by nicotinic cholinergic receptors (nAChR). However, nicotinic receptor subtypes and functions in the bladder are not clearly identified. Purpose: This study aimed at investigating the effect of varenicline, an alpha7 full agonist and alpha4beta2/alpha3 partial agonist, on detrusor strips in rat PD model induced by substantia nigra injection of 6-hydroxydopamine. Method: The detrusor activity was studied in an isolated organ bath system. Results: In PD group, the detrusor activity was increased, whereas varenicline decreased the DO. Conclusion: Alpha7 nAChR agonists may have therapeutic potential in treatment of bladder overactivity in PD.

Exercise improves the body function and protects the neuronal injury in Parkinson's disease rats by activating calpain 1 and kallikrein 6.

Parkinson's disease (PD) is a neurodegenerative disease, which alters body and cognitive functions. The present study evaluates the effect of exercise on body function and neuronal injury against a 6-hydroxydopamine hydrobromide (6-OHDA) induced PD rat model and postulates a possible molecular mechanism of its action. Parkinson's disease was induced by administration of (20 µg/5 µl at the rate of 1 µl/min) 6-OHDA and exercise training was given to mice by motorized rodent treadmill for a period of 14 days after the confirmation of PD. Behavioural changes were observed by apomorphine-induced rotation and motor function was assessed using the rotarod apparatus. The effect of exercise was observed on the levelof neurochemicals and the expression of calpain-1 (CAPN1) and kallikrein 6 (KLK6) was estimated in brain tissue of PD rats using western blot assay. A more significant improvement in the motor and cognitive function was observed in the PD + exercise group than in the PD group of rats. Exercise attenuates the altered level of g-aminobutyric acid (GABA), dopamine (DA) and glutamate in brain tissue of PD rats. Intracellular concentration of Ca+ ion was reduced significantly in brain tissue of the PD + exercise group compared to PD rats. Moreover, exercise activates the expression of KLK6 and CAPN1 protein in brain tissue of PD rats. In conclusion, data of the study reveal that exercise protects neuronal injury by reducing intracellular concentration Ca+ ion and activates KLK6 and CAPN1 in brain tissue of PD rats and thereby improves motor and cognitive functions.

Effect of Nelumbo nucifera rhizome extract in haloperidol induced Parkinson rat model

Effect of Nelumbo nucifera rhizome extract in haloperidol induced Parkinson rat model

Imaging of cerebral tryptophan metabolism using 7-[18F]FTrp-PET in a unilateral Parkinsonian rat model

Degradation products of the essential amino acid tryptophan (Trp) are important signaling molecules in the mammalian brain. Trp is metabolized either through the kynurenine pathway or enters serotonin and melatonin syntheses. The aim of the present work was to examine the potential of the novel PET tracer 7-[18F]fluorotryptophan ([18F]FTrp) to visualize all three pathways in a unilateral 6-OHDA rat model. [18F]FDOPA-PET scans were performed in nine 6-OHDA-injected and six sham-operated rats to assess unilateral dopamine depletion severity four weeks after lesion placement. Afterwards, 7-[18F]FTrp-PET scans were conducted at different timepoints up to seven months after 6-OHDA injection. In addition, two 6-OHDA-injected rats were examined for neuroinflammation using [18F]DAA1106-PET. 7-[18F]FTrp-PET showed significantly increased tracer uptake at the 6-OHDA injection site which was negatively correlated to time after lesion placement. Accumulation of [18F]DAA1106 at the injection site was increased as well, suggesting that 7-[18F]FTrp uptake in this region may reflect kynurenine pathway activity associated with inflammation. Bilaterally in the dorsal hippocampus, 7-[18F]FTrp uptake was significantly decreased and was inversely correlated to dopamine depletion severity, indicating that it reflects reduced serotonin synthesis. Finally, 7-[18F]FTrp uptake in the pineal gland was significantly increased in relation with dopamine depletion severity, providing evidence that melatonin synthesis is increased in the 6-OHDA rat model. We conclude that 7-[18F]FTrp is able to detect alterations in both serotonin/melatonin and kynurenine metabolic pathways, and can be applied to visualize pathologic changes related to neurodegenerative processes.

Upregulated mGluR5 induces ER stress and DNA damage by regulating the NMDA receptor subunit NR2B.

Dysfunction caused by mGluR5 expression or activation is an important mechanism in the development of Parkinson's disease (PD). Early clinical studies on mGluR5 negative allosteric modulators have shown some limitations. It is therefore necessary to find a more specific approach to block mGluR5-mediated neurotoxicity. Here, we determined the role of N-methyl-D-aspartate (NMDA) receptor subunit NR2B in mGluR5-mediated ER stress and DNA damage. In vitro study, rotenone-induced ER stress and DNA damage were accompanied by an increase in mGluR5 expression and overexpressed or activated mGluR5 with agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) induced ER stress and DNA damage, while blocking mGluR5 with antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) alleviated the effect. Furthermore, the damage caused by CHPG was blocked by NMDA receptor antagonist MK-801. Additionally, rotenone or CHPG increased the p-Src and p-NR2B, which was inhibited by MPEP. Blocking p-Src or NR2B with PP2 or CP101,606 alleviated CHPG-induced ER stress and DNA damage. Overactivation of mGluR5 accompanied with the increase of p-Src and p-NR2B in the ER stress and DNA damage was found in rotenone-induced PD rat model. These findings suggest a new mechanism wherein mGluR5 induces ER stress and DNA damage through the NMDA receptor and propose NR2B as the molecular target for therapeutic strategy for PD.

α-Synuclein Overexpression Increases Dopamine D2/3 Receptor Binding and Immune Activation in a Model of Early Parkinson's Disease.

Progressive degeneration of dopaminergic neurons, immune activation, and α-synuclein pathology characterize Parkinson’s disease (PD). We previously reported that unilateral intranigral injection of recombinant adeno-associated viral (rAAV) vectors encoding wild-type human α-synuclein produced a rat model of early PD with dopamine terminal dysfunction. Here we tested the hypothesis that decreases in dopamine result in increased postsynaptic dopamine D2/D3 receptor expression, neuroinflammation, and reduced synaptic vesicle glycoprotein 2A (SV2A) density. Rats were injected with rAAV encoding α-synuclein or green fluorescent protein and subjected to non-pharmacological motor tests, before euthanization at 12 weeks post-injection. We performed: (1) in situ hybridization of nigral tyrosine hydroxylase mRNA, (2) HPLC of striatal dopamine content, and (3) autoradiography with [3H]raclopride, [3H]DTBZ, [3H]GBR12935, [3H]PK11195, and [3H]UCB-J to measure binding at D2/3 receptors, vesicular monoamine transporter 2, dopamine transporters, mitochondrial translocator protein, and SV2A, respectively. rAAV-α-synuclein induced motor asymmetry and reduced tyrosine hydroxylase mRNA and dopamine content in ipsilateral brain regions. This was paralleled by elevated ipsilateral postsynaptic dopamine D2/3 receptor expression and immune activation, with no changes to synaptic SV2A density. In conclusion, α-synuclein overexpression results in dopaminergic degeneration that induced compensatory increases in D2/3 binding and immune activation, recapitulating many of the pathological characteristics of PD.

Predictive accuracy of CNN for cortical oscillatory activity in an acute rat model of parkinsonism

In neurological and neuropsychiatric disorders neuronal oscillatory activity between basal ganglia and cortical circuits are altered, which may be useful as biomarker for adaptive deep brain stimulation. We investigated whether changes in the spectral power of oscillatory activity in the motor cortex (MCtx) and the sensorimotor cortex (SMCtx) of rats after injection of the dopamine (DA) receptor antagonist haloperidol (HALO) would be similar to those observed in Parkinson disease. Thereafter, we tested whether a convolutional neural network (CNN) model would identify brain signal alterations in this acute model of parkinsonism. A sixteen channel surface micro-electrocorticogram (ECoG) recording array was placed under the dura above the MCtx and SMCtx areas of one hemisphere under general anaesthesia in rats. Seven days after surgery, micro ECoG was recorded in individual free moving rats in three conditions: (1) basal activity, (2) after injection of HALO (0.5 mg/kg), and (3) with additional injection of apomorphine (APO) (1 mg/kg). Furthermore, a CNN-based classification consisting of 23,530 parameters was applied on the raw data. HALO injection decreased oscillatory theta band activity (4–8 Hz) and enhanced beta (12–30 Hz) and gamma (30–100 Hz) in MCtx and SMCtx, which was compensated after APO injection (P ¡ 0.001). Evaluation of classification performance of the CNN model provided accuracy of 92%, sensitivity of 90% and specificity of 93% on one-dimensional signals. The CNN proposed model requires a minimum of sensory hardware and may be integrated into future research on therapeutic devices for Parkinson disease, such as adaptive closed loop stimulation, thus contributing to more efficient way of treatment.

Iron status, immune system, and expression of brain divalent metal transporter 1 and dopamine receptors D1 interrelationship in Parkinson’s disease and the role of grape seed and green coffee bean extracts and quercetin in mitigating the disease in rats

Introduction: Parkinson’s disease (PD) is a neurodegenerative disease with a prevalence of 1% in the elderly worldwide. The aim of the research is to study the interrelationship of iron status, the immune system including inflammatory cytokines, brain divalent metal transporter 1 (DMT1), and dopamine receptors D1 (DRD1) in a PD rat model. The potential protective effects of grape seed and green coffee bean ethanol extracts and quercetin were also studied. Methods: Phenolic and flavonoid contents of grape seed and green coffee bean and in vitro free radicals scavenging activities of the extracts and quercetin were determined. Male rats were divided into five groups. Group 1 served as normal control (NC), group 2 represented Parkinsonian control (PC). Groups 3, 4, and 5 were the test groups treated by daily oral green coffee bean, grape seed extracts, and quercetin, respectively. PD was induced by rotenone in groups 2 to 5. Brain oxidative stress, DMT1, and DRD1 expressions, and histopathology were assessed. Parameters of the immune system, represented by plasma interferon-gamma (IFNγ) and CD4, and brain tumor necrosis factor-alpha (TNF-α) along with iron status were also determined. Results: Phenolic and flavonoid contents of green coffee bean were high compared to grape seed (P &lt; 0.05). Quercetin experienced the highest in-vitro free radicals scavenging activities. Iron deficiency anemia, together with elevated IFNγ, TNF-α, DMT1 expressions, and brain malondialdehyde (MDA) were demonstrated in PC compared to NC (P &lt; 0.05). Also, reduction in CD4 and brain reduced-glutathione (GSH) (P &lt; 0.05) were noticed in PC with brain histopathological alterations. Different treatments showed variable improvements in the majority of parameters (P &lt; 0.05) and brain histopathology. Conclusion: Iron deficiency anemia might result from cytokine elevation in PD. Reduced DRD1 and altered immune system including cytokines together with increased brain DMT1 might induce neurodegeneration in PD. Different treatments showed variable neuroprotective effects through modulation of inflammation, oxidative stress, immune system, iron status, DMT1, and DRD1.

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease.

Cell therapy is a promising treatment for Parkinson’s disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons. 6-OHDA lesioned Sprague Dawley rats received intra-striatal grafts of dopaminergic ventral mesencephalic cells from embryonic day 14 Wistar rat embryos. Transplanted rats then received either saline or L-dopa (12 mg/kg) administered every 48 h prior to, and following cell transplantation. Peripheral GLP-1R agonist administration (exendin-4, 0.5 μg/kg twice daily or liraglutide, 100 μg/kg once daily) commenced immediately after cell transplantation and was maintained throughout the study. Graft survival increased under administration of exendin-4, with motor function improving significantly following treatment with both exendin-4 and liraglutide. However, this effect was not observed in rats administered with L-dopa. In contrast, L-dopa treatment with liraglutide increased graft volume, with parallel increases in motor function. However, this improvement was accompanied by an increase in leukocyte infiltration around the graft. The co-administration of L-dopa and exendin-4 also led to indicators of insulin resistance not seen with liraglutide, which may underpin the differential effects observed between the two GLP1-R agonists. Overall, there may be some benefit to the supplementation of grafted patients with GLP-1R agonists but the potential interaction with other pharmacological treatments needs to be considered in more depth.

Identification of effective features of LFP signal for making closed-loop deep brain stimulation in parkinsonian rats.

Traditional deep brain stimulation (DBS) is one of the acceptable methods to relieve the clinical symptoms of Parkinson's disease in its advanced stages. Today, the use of closed-loop DBS to increase stimulation efficiency and patient satisfaction is one of the most important issues under investigation. The present study was aimed to find local field potential (LFP) features of parkinsonian rats, which can determine the timing of stimulation with high accuracy. The LFP signals from rats were recorded in three groups of parkinsonian rat models receiving stimulation (stimulation), without getting stimulation (off-stimulation), and sham-controlled group. The frequency domain and chaotic features of signals were extracted for classifying three classes by support vector machine (SVM) and neural networks. The best combination of features was selected using the genetic algorithm (GA). Finally, the effective features were introduced to determine the on/off stimulation time, and the optimal stimulation parameters were identified. It was found that a combination of frequency domain and chaotic features with an accuracy of about 99% was able to determine the time the DBS must switch on. In about 80.67% of the 1861 different stimulation parameters, the brain was able to maintain its state for about 3 min after stimulation discontinuation.

Manipulation of vocal communication and anxiety through pharmacologic modulation of norepinephrine in the Pink1-/- rat model of Parkinson disease

Vocal deficits and anxiety are common, co-occurring, and interacting signs of Parkinson Disease (PD) that have a devastating impact on quality of life. Both manifest early in the disease process. Unlike hallmark motor signs of PD, neither respond adequately to dopamine replacement therapies, suggesting that their disease-specific mechanisms are at least partially extra-dopaminergic. Because noradrenergic dysfunction is also a defining feature of PD, especially early in the disease progression, drug therapies targeting norepinephrine are being trialed for treatment of motor and non-motor impairments in PD. Research assessing the effects of noradrenergic manipulation on anxiety and vocal impairment in PD, however, is sparse. In this pre-clinical study, we quantified the influence of pharmacologic manipulation of norepinephrine on vocal impairment and anxiety in Pink1-/- rats, a translational model of PD that demonstrates both vocal deficits and anxiety. Ultrasonic vocalization acoustics, anxiety behavior, and limb motor activity were tested twice for each rat: after injection of saline and after one of three drugs. We hypothesized that norepinephrine reuptake inhibitors (atomoxetine and reboxetine) and a β receptor antagonist (propranolol) would decrease vocal impairment and anxiety compared to saline, without affecting spontaneous motor activity. Our results demonstrated that atomoxetine and reboxetine decreased anxiety behavior. Atomoxetine also modulated ultrasonic vocalization acoustics, including an increase in vocal intensity, which is almost always reduced in animal models and patients with PD. Propranolol did not affect anxiety or vocalization. Drug condition did not influence spontaneous motor activity. These studies demonstrate relationships among vocal impairment, anxiety, and noradrenergic systems in the Pink1-/- rat model of PD.

The 6-hydroxydopamine Rat Model of Parkinson's Disease.

Motor symptoms of Parkinson's disease (PD)-bradykinesia, akinesia, and tremor at rest-are consequences of the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and dopaminergic striatal deficit. Animal models have been widely used to simulate human pathology in the laboratory. Rodents are the most used animal models for PD due to their ease of handling and maintenance. Moreover, the anatomy and molecular, cellular, and pharmacological mechanisms of PD are similar in rodents and humans. The infusion of the neurotoxin, 6-hydroxydopamine (6-OHDA), into a medial forebrain bundle (MFB) of rats reproduces the severe destruction of dopaminergic neurons and simulates PD symptoms. This protocol demonstrates how to perform the unilateral microinjection of 6-OHDA in the MFB in a rat model of PD and shows the motor deficits induced by 6-OHDA and predicted dopaminergic lesions through the stepping test. The 6-OHDA causes significant impairment in the number of steps performed with the contralateral forelimb.