6-OHDA Rats Research Articles

Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.

Effect of hemodynamic characteristic changes of the carotid artery on 6-OHDA-induced Parkinson’s disease model rats treated by Gut-acupuncture

BackgroundBased on “gut-brain axis” theory, we employed a rat 6-OHDA lesion model to examine the impact of gut-acupuncture on motor symptoms, the abundance of DA neurons in the SN, the hemodynamic characteristics of the carotid artery and SNH. Methods6-OHDA-induced PD rats were treated with gut-acupuncture daily, starting day 15 after surgery. Mobility of the limbs was evaluated, abundance of TH + DA neurons in the SN detected, The diameter of carotid arteries and hemodynamic parameters measured by cervical vascular ultrasound CVUS, and TCS utilized to examine SNH. ResultsOur data show that gut-acupuncture correlates with significantly increased abundance of TH, a marker of DA neurons compared to untreated rats. Furthermore the area of SNH in the injured side of the acupuncture group was significantly reduced. PSV of LCCA, LICA, RICA showed that were significantly improved i.e. decreased in the acupuncture group, while the diameter of LICA and RCCA in acupuncture group was narrower. We also found that the PSV was significantly increased and the vascular diameter narrowed in LCCA and LICA during treatment, whereas after removing the acupuncture needle the PSV decreased and the vascular diameter widened. ConclusionsGut-acupuncture can reduce SNH and influence TH abundance in the SN which correlated with changes of hemodynamic characteristics of the lesioned side. We suggest a regulatory mechanism which may affect the vagus nerve through the ENS and cause the change of cervical hemodynamics. It further induces low oxygen tension microenvironment conducive to the proliferation of neural stem cells, which leads to the enrichment of TH in PD model rats of acupuncture group.

The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism

The dynamical properties of cortico-basal ganglia (CBG) circuits are dramatically altered following the loss of dopamine in Parkinson’s disease (PD). The neural circuit dysfunctions associated with PD include spike-rate alteration concomitant with excessive oscillatory spike-synchronization in the beta frequency range (12–30 Hz). Which neuronal circuits orchestrate and propagate these abnormal neural dynamics in CBG remains unknown. In this work, we combine in vivo electrophysiological recordings with advanced optogenetic manipulations in normal and 6-OHDA rats to shed light on the mechanistic principle underlying circuit dysfunction in PD. Our results show that abnormal neural dynamics present in a rat model of PD do not rely on cortical or subthalamic nucleus activity but critically dependent on globus pallidus (GP) integrity. Our findings highlight the pivotal role played by the GP which operates as a hub nucleus capable of orchestrating firing rate and synchronization changes across CBG circuits both in normal and pathological conditions.

Parkinsonism and subthalamic deep brain stimulation dysregulate behavioral motivation in a rodent model

BackgroundApathy and impulsivity constitute opposite poles of a behavioral motivation spectrum often disrupted by both the symptoms and therapies for Parkinson’s Disease (PD). Upwards of 70% of PD patients experience symptoms of apathy, frequently unresolved or worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Worse, more than half of patients receiving DBS for PD experience new-onset impulse control disorders of varying severity following therapy initiation. While these symptoms and side-effects have been widely reported in clinical studies, they are largely unexplored in animal models. MethodsWe applied high-frequency DBS in a 6-OHDA hemiparkinsonian rat model. We trained rats on a series of go/stop and go/no-go behavioral paradigms and examined how parkinsonism and DBS modulated task responses. ResultsSTN DBS in healthy rodents drove impulsive behavior in the form of stop and no-go task failure, impulsive reward seeking, and noninstructed task attempts. While trained rats without DBS only tended to fail stop and no-go cues very shortly after the cue, DBS led to failures at significantly later time points. Hemiparkinsonism slowed response times and reduced response rates, not alleviated by effective DBS. InterpretationsPD interrupts neural signaling responsible for healthy action selection, not restored by DBS. PD may be associated with a dearth of action commands, manifesting as apathy. Conversely, effective DBS may bias the system toward the impulsive end of the behavioral motivation spectrum without restoring behaviorally reasonable actions, mis-weighting reward-based action selection and manifesting as impulsivity, aided by DBS interfering with stop signaling.

Respiratory pattern and phrenic and hypoglossal nerve activity during normoxia and hypoxia in 6-OHDA-induced bilateral model of Parkinson\u2019s disease

Respiratory disturbances present in Parkinson’s disease (PD) are not well understood. Thus, studies in animal models aimed to link brain dopamine (DA) deficits with respiratory impairment are needed. Adult Wistar rats were lesioned with injection of 6-hydroxydopamine (6-OHDA) into the third cerebral ventricle. Two weeks after hypoxic test was performed in whole-body plethysmography chamber, phrenic (PHR) and hypoglossal (HG) nerve activities were recorded in normoxic and hypoxic conditions in anesthetized, vagotomized, paralyzed and mechanically ventilated rats. The effects of activation and blockade of dopaminergic carotid body receptors were investigated during normoxia in anesthetized spontaneously breathing rats. 6-OHDA injection affected resting respiratory pattern in awake animals: an increase in tidal volume and a decrease in respiratory rate had no effect on minute ventilation. Hypoxia magnified the amplitude and minute activity of the PHR and HG nerve of 6-OHDA rats. The ratio of pre-inspiratory to inspiratory HG burst amplitude was reduced in normoxic breathing. Yet, the ratio of pre-inspiratory time to total time of the respiratory cycle was increased during normoxia. 6-OHDA lesion had no impact on DA and domperidone effects on the respiratory pattern, which indicate that peripheral DA receptors are not affected in this model. Analysis of monoamines confirmed substantial striatal depletion of dopamine, serotonin and noradrenaline (NA) and reduction of NA content in the brainstem. In bilateral 6-OHDA model changes in activity of both nerves: HG (linked with increased apnea episodes) and PHR are present. Demonstrated respiratory effects could be related to specific depletion of DA and NA.

Ameliorative effects of a phosphodiesterase 10A inhibitor, MR1916 on L-DOPA-induced dyskinesia in parkinsonian rats.

Dopamine replacement therapy using L-3,4-dihydroxyphenylalanine (L-DOPA) is a gold standard treatment in patients with Parkinson's disease (PD); however, chronic administration of L-DOPA causes excessive involuntary movements called L-DOPA-induced dyskinesia. Therefore, the novel pharmacological treatment is needed. We examined the antidyskinetic effect of a phosphodiesterase 10A (PDE10A) inhibitor, MR1916 and a currently available antidyskinetic drug, amantadine in unilateral 6-OHDA lesioned rats exhibited stably dyskinesia after chronic administration of L-DOPA. We also examined the influence of MR1916 and amantadine on the improvement of forelimb akinesia induced by L-DOPA using stepping test in unilateral 6-OHDA lesioned rats. MR1916 (0.03‒0.3mg/kg, po) reduced L-DOPA-induced dyskinesia in a dose-dependent manner and showed significant effects at doses of 0.1 and 0.3mg/kg, while amantadine (40mg/kg, sc) had no remarkable effects. Neither MR1916 (0.03‒0.3mg/kg, po) nor amantadine (40mg/kg, sc) affected the antiparkinsonian effects induced by L-DOPA in unilateral 6-OHDA lesioned rats. These results indicate that MR1916 specifically reduces L-DOPA-induced dyskinesia without affecting the antiparkinsonian effect of L-DOPA in parkinsonian rats.

Assessment of vitamin D and inflammatory markers profile in cardiac tissue on Parkinson disease animal model.

Cardiovascular dysfunctions are common non-motor symptoms in patients with Parkinson's disease (PD) that can result in reduced quality of life and even death. Research in animal models designed to characterize the pathological association between PD and cardiovascular abnormalities is still in its infancy. This study assessed the early impact of the nigrostriatal dopaminergic damage on cardiological features in the unilateral 6-OHDA rat model of PD. Male Wistar rats received unilateral intrastriatal injections of 6-OHDA and sham rats were injected with saline. Animals were studied 15days later. Immunohistochemistry was used for visualization of tyrosine hydroxylase (TH)-positive neurons in the nigrostriatal system. Electrocardiogram recordings of heart rate were performed in conscious rats. Heart levels of vitamin D, inflammatory cytokines and C-reactive protein were assessed through electrochemiluminescence immunoassay, quantitative reverse transcription PCR and turbidimetric method, respectively. We found a post-injury reduction of TH-immunoreactivity of approximately 45% in the substantia nigra pars compacta and 20% in the striatum. Heart rate reduction was found in 6-OHDA-lesioned rats as compared with sham counterparts. Reduced levels of vitamin D and increased levels of inflammatory factors (C-reactive protein, IL-6, TNF-α and TGF-β) were detected in the heart tissue of PD rats in comparison with sham. Our findings suggest a link between cardiac tissue changes and cardiac functional changes early after the central dopaminergic damage induced by 6-OHDA. Knowledge of the cardiac abnormalities in the 6-OHDA model is critical in identifying future therapeutic targets and disease-modifying approaches for PD non-motor features.

Pathological remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration

Background and aimPatients with Parkinson's disease (PD) are often characterized by functional gastrointestinal disorders. Such disturbances can occur at all stages of PD and precede the typical motor symptoms of the disease by many years. However, the morphological alterations associated with intestinal disturbances in PD are undetermined. This study examined the remodelling of colonic wall in 6-hydroxydopamine (6-OHDA)-induced PD rats. Methods8 weeks after 6-OHDA injection animals were sacrificed. Inflammatory infiltrates, collagen deposition and remodelling of intestinal epithelial barrier and tunica muscularis in the colonic wall were assessed by histochemistry, immunohistochemistry, immunofluorescence and western blot analysis. Results6-OHDA rats displayed significant alterations of colonic tissues as compared with controls. Signs of mild inflammation (eosinophil infiltration) and a transmural deposition of collagen fibres were observed. Superficial colonic layers were characterized by severe morphological alterations. In particular, lining epithelial cells displayed a reduced claudin-1 and transmembrane 16A/Anoctamin 1 (TMEM16A/ANO1) expression; goblet cells increased their mucin expression; colonic crypts were characterized by an increase in proliferating epithelial cells; the density of S100-positive glial cells and vimentin-positive fibroblast-like cells was increased as well. Several changes were found in the tunica muscularis: downregulation of α-smooth muscle actin/desmin expression and increased proliferation of smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia; reduction of interstitial cells of Cajal (ICCs) density. ConclusionsA pathological remodelling occurs in the colon of 6-OHDA rats. The main changes include: enhanced fibrotic deposition; alterations of the epithelial barrier; activation of mucosal defense; reduction of ICCs. These results indicate that central nigrostriatal denervation is associated with histological changes in the large bowel at mucosal, submucosal and muscular level. These alterations might represent morphological correlates of digestive symptoms in PD.

P.105 The study of molecular changes induced by CPL500-036, a potential novel anti-dyskinetic drug, in 6-OHDA rat model of Parkinson's disease

P.105 The study of molecular changes induced by CPL500-036, a potential novel anti-dyskinetic drug, in 6-OHDA rat model of Parkinson's disease

Electroacupuncture alleviates Parkinson disease and regulates the expression of brain-gut peptides.

The non-motor symptoms (NMS) of Parkinson’s disease (PD) are found in more than 90% of patients with PD. Here, we explored the effects of electroacupuncture (EA) stimulation at Zhong wan (CV-12), Qihai (RN-7), Zusanli (ST-36) and Taichong (LR-3) on NMS and brain-gut peptides of PD. We found that EA intervention alleviated the motor deficit induced by 6-OHDA in rats indicated by the decreased abnormal involuntary movements (AIMs) scores and the net number of rotations and increased cylinder test grade. It also improved the spatial memory and attenuated anxiety-like and depression of PD model rats. EA treatment significantly inhibited neuronal apoptosis in PD model animals, as demonstrated by the increased number of TH positive cells and reduced number of apoptotic cells in the substantia nigra. The expression of cleaved caspase-3 and cleaved PARP in PD model rats was markedly suppressed by EA stimulation. Moreover, EA remarkably inhibited the inflammatory response in PD model rats, as revealed by the decreased levels of TNF-α, IL-1β, and COX-2 mRNA expression. It also attenuated the oxidative stress in rats, as indicated by the increased levels of SOD and GSH and the decreased level of MDA. EA treatment contributed to alleviating PD by regulating brain-gut peptides in rats, such as NPY, CCK, SST, GAS, and PYY. In conclusion, EA stimulation at CV-12, RN-7, ST-36, and LR-3 effectively alleviates the NMS of PD partly through regulating the levels of brain-gut peptides.

The Effect of Focused Transcranial Magnetic Stimulation on Behavioral Profiles and Motor Cortex Signals in the Animal Model of Parkinsonism

Background: Non-invasive magnetic stimulation therapies have become a widespread neuromodulation method utilized in the treatment of mood disorders. Although these methods have shown efficacy in the treatment of psychiatric disorders such as bipolar affective disorder and depression, a few studies have been done on Parkinson's disease (PD). Objective: This study was executed to demonstrate the effectiveness of focused transcranial magnetic stimulation (fTMS) for the treatment of PD. For this aim, a new stimulation coil design with the semi-hexagonal core was used to concentrate magnetic flux in the particular innervation nucleus. Several TMS protocols were tested to stimulate the STN region of 6-OHDA lesioned rats to determine the most effective treatment. Results: The progress of treatment was investigated by recording and analyzing the neurophysiological activity of the primary motor cortex and locomotor behaviors. After 6-OHDA injection, sharp increases in the energy and power spectral density of beta and low- gamma band were caused. Also, the motor activities of rats reduced, and the degree of catalepsy increased significantly. By completing the proposed 1Hz r-TMS treatment, the amount of energy and power density in these bands diminished and came close to the baseline. Furthermore, debilitating motor fluctuations were reverted considerably. Conclusion: Experimental results reveal that after 40 days of the non-invasive procedure, both oscillatory activity and the locomotor behavior produce remarkable changes. The 1Hz r-TMS showed acceptable performance in a reduction of symptoms in the PD. The outcomes of the animal trials have raised some hopes to employ the findings of this study in human clinical research.

Bilateral Intracranial Beta Activity During Forced and Spontaneous Movements in a Hemi-PD Rat Model

Cortico-basal ganglia beta oscillations (13-30Hz) are assumed to be involved in motor impairments in Parkinson’s Disease (PD), especially in bradykinesia and rigidity. Various studies have utilized the unilateral 6-OHDA rat PD model to further investigate PD and test novel treatments. However, a detailed behavioral and electrophysiological characterization of the model, including analyses of popular PD treatments such as DBS, has not been documented in the literature. We hence challenged the 6-OHDA rat PD model with a series of experiments (i.e. cylinder test, open field test and rotarod test) aimed at assessing the motor impairments, analyzing the effects of Deep Brain Stimulation (DBS), and identifying under which conditions excessive beta oscillations occur. We found that hemi-PD rats presented an impaired performance in all experiments compared to the sham group, and DBS could improve their overall performance. Across all the experiments and behaviors, the power in the high beta band was observed to be an important biomarker for PD as it showed differences between healthy and lesioned hemispheres and between PD and sham rats. This all shows that the 6-OHDA PD model accurately represents many of the motor and electrophysiological symptoms of PD and makes it a useful tool for the pre-clinical testing of new treatments when low β (13-21Hz) and high β (21-30Hz) frequency bands are considered separately.

The Association Between Parkinson’s Disease and Attention-Deficit Hyperactivity Disorder

While Parkinson’s disease (PD) and attention-deficit hyperactivity disorder (ADHD) are two distinct conditions, it has been hypothesized that they share several overlapping anatomical and neurochemical changes. In order to investigate that hypothesis, this study used claims data from Taiwan’s Longitudinal Health Insurance Database 2000 to provide the significant nationwide population-based evidence of an increased risk of PD among ADHD patients, and the connection between the two conditions was not the result of other comorbidities. Moreover, this study showed that the patients with PD were 2.8 times more likely to have a prior ADHD diagnosis compared with those without a prior history of ADHD. Furthermore, an animal model of ADHD was generated by neonatally injecting rats with 6-hydroxydopamine (6-OHDA). These rats were subjected to behavior tests and the 99mTc-TRODAT-1 brain imaging at the juvenile stage. Compared to control group rats, the 6-OHDA rats showed a significantly reduced specific uptake ratio in the striatum, indicating an underlying PD-linked pathology in the brains of these ADHD phenotype-expressing rats. Overall, these results support that ADHD shares a number of anatomical and neurochemical changes with PD. As such, improved knowledge of the neurochemical mechanisms underlying ADHD could result in improved treatments for various debilitating neurological disorders, including PD.

In vivo validation of a new portable stimulator for chronic deep brain stimulation in freely moving rats

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered as a gold standard therapy for the alleviation of motor symptoms in Parkinson’s disease (PD). This success paved the way to its application for other neurological and psychiatric disorders. In this context, we aimed to develop a rodent-specific stimulator with characteristics similar to those used in patients. New methodWe designed a stimulator that can be connected to an electrode container with options for bilateral or unilateral stimulation selection and offers a wide range of frequencies, pulse widths and intensities, constant current, biphasic current-control and charge balancing. Dedicated software was developed to program these parameters and the device was tested on a bilateral 6-hydroxydopamine (6-OHDA) rat model of PD. ResultsThe equipment was well tolerated by the animals with a good general welfare. STN stimulation (130 Hz frequency, 0.06 ms pulse width, 150 μA average intensity) improved the motor deficits induced by 6-OHDA as it significantly increased the number of movements compared to the values obtained in the same animals without STN stimulation. Furthermore, it restored motor coordination by significantly increasing the time spent on the rotarod bar. ConclusionWe successfully developed and validated a new portable and programmable stimulator for freely moving rats that delivers a large range of stimulation parameters using bilateral biphasic current-control and charge balancing to maximize tissue safety. This device can be used to test deep brain stimulation in different animal models of human brain diseases.

Epidural Spinal Cord Stimulation Improves Motor Function in Rats With Chemically Induced Parkinsonism

Background. Epidural stimulation of the spinal cord can reorganize and change the excitability of the neural circuitry to facilitate stepping in rats with a complete spinal cord injury. Parkinson’s disease results in abnormal supraspinal signals from the brain to the spinal cord that affect the functional capacity of the spinal networks. Objective. The objective was to determine whether epidural stimulation (electrical enabling motor control, eEmc) of the lumbosacral spinal cord can reorganize the spinal networks to facilitate hindlimb stepping of rats with parkinsonism. Methods. A unilateral 6-OHDA (6-hydroxydopamine) lesion of the nigrostriatal pathway was used to induce parkinsonism. Sham rats (N = 4) were injected in the same region with 0.1% of ascorbic acid. Stimulation electrodes were implanted epidurally at the L2 and S1 (N = 5) or L2 (N = 5) spinal levels. Results. The 6-OHDA rats showed severe parkinsonism in cylinder and adjusting step tests and were unable to initiate stepping when placed in a running wheel and dragged their toes on the affected side during treadmill stepping. During eEmc, the 6-OHDA rats initiated stepping in the running wheel and demonstrated improved stepping quality. Conclusion. Stepping was facilitated in rats with parkinsonism with spinal cord stimulation. The underlying assumption is that the normal functional capacity of spinal networks is affected by supraspinal pathology associated with Parkinson’s disease, which either generates insufficient or abnormal descending input to spinal networks and that eEmc can appropriately modulate spinal and supraspinal networks to improve the motor deficits.

Bone Marrow Mesenchymal Stem Cells' Secretome Exerts Neuroprotective Effects in a Parkinson's Disease Rat Model.

Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

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.

Intranasal delivery of low-dose insulin ameliorates motor dysfunction and dopaminergic cell death in a 6-OHDA rat model of Parkinson’s Disease

Emerging evidence continues to demonstrate that disrupted insulin signaling and altered energy metabolism may play a key role underpinning pathology in neurodegenerative conditions. Intranasally administered insulin has already shown promise as a memory-enhancing therapy in patients with Alzheimer’s and animal models of the disease. Intranasal drug delivery allows for direct targeting of insulin to the brain, bypassing the blood brain barrier and minimizing systemic adverse effects. In this study, we sought to expand upon previous results that show intranasal insulin may also have promise as a Parkinson’s therapy. We treated 6-OHDA parkinsonian rats with a low dose (3 IU/day) of insulin and assessed apomorphine induced rotational turns, motor deficits via a horizontal ladder test, and dopaminergic cell survival via stereological counting. We found that insulin therapy substantially reduced motor dysfunction and dopaminergic cell death induced by unilateral injection of 6-OHDA. These results confirm insulin’s efficacy within this model, and do so over a longer period after model induction which more closely resembles Parkinson’s disease. This study also employed a lower dose than previous studies and utilizes a delivery device, which could lead to an easier transition into human clinical trials as a therapeutic for Parkinson’s disease.

Voltage-Gated Sodium Channels Are Involved in Cognitive Impairments in Parkinson's Disease- like Rats

Cognitive impairment is one of the common non-motor symptoms in Parkinson's disease (PD). The hippocampus is a critical structure for learning and memory processes. The abnormal synaptic plasticity in the hippocampus is suggested to be associated with cognitive dysfunction in PD. Voltage gated sodium channels (VGSCs) are key molecules involved in synaptic transmission in the nervous system. Here, the expression patterns of VGSC subtypes Nav1.1, Nav1.3, Nav1.6 in the hippocampus of 6-hydroxydopamine (6-OHDA) lesioned rats were investigated at different time points after 6-OHDA injection. The results showed that the expression of Nav1.1 was remarkably increased in reactive astrocytes at 28days, whereas was sharply reduced at 49days after 6-OHDA injection. However, the expression of Nav1.6 was not different from the control hippocampus at 28days, but was abundantly increased in neurons of the contralateral and ipsilateral hippocampus at 49days after 6-OHDA injection. Moreover, Nav1.3, a subtype predominantly expressed at embryonic stage, was scatteredly re-expressed in neurons of the CA area in the contralateral and ipsilateral hippocampus at 49days after 6-OHDA injection. Furthermore, spatial learning and memory in 6-OHDA lesioned rats were effectively improved by acute treatment with a VGSCs blocker, phenytoin. These findings suggested that VGSCs may play an important role in the genesis of cognitive deficits in PD.

Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson’s disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder caused by the loss of midbrain dopamine (DA) neurons. While the cause of DA cell loss in PD is unknown, male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex-chromosome genes contribute to the male bias in PD. We previously showed that the Y-chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement. Here we demonstrate that nigral SRY expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral SRY expression with antisense oligonucleotides in male rats diminished motor deficits and nigral DA cell loss in 6-hydroxydopamine (6-OHDA)-induced and rotenone-induced rat models of PD. The protective effect of the SRY antisense oligonucleotides was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD. Moreover, reducing nigral SRY expression diminished or removed the male bias in nigrostriatal degeneration, mitochondrial degradation, DNA damage, and neuroinflammation in the 6-OHDA rat model of PD, suggesting that SRY directly contributes to the sex differences in PD. These findings demonstrate that SRY directs a previously unrecognized male-specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex-specific strategy to slow or prevent DA cell loss in PD.