Rodent Models Of Parkinson's Disease Research Articles

Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls

The dopamine agonist pramipexole (PPX) can increase impulsiveness, and PPX therapy for neurological diseases (Parkinson's disease (PD) and restless leg syndrome) is associated with impulse control disorders (ICDs) in subpopulations of treated patients. A commonly reported ICD is pathological gambling of which risk taking is a prominent feature. Probability discounting is a measurable aspect of risk taking. We recently developed a probability discounting paradigm wherein intracranial self-stimulation (ICSS) serves as the positive reinforcer. Here we used this paradigm to determine the effects of PPX on discounting. We included assessments of a rodent model of PD, wherein 6-OHDA was injected into the dorsolateral striatum of both hemispheres, which produced persistent PD-like deficits in posture adjustment. Rats were trained to perform ICSS-mediated probability discounting, in which PD-like and control groups exhibited similar profiles. Rats were treated twice daily for 2 weeks with 2 mg/kg (±)PPX (ie, 1 mg/kg of the active form), a dose that improved lesion-induced motor deficits. In both groups, (±)PPX increased discounting; preference for the large reinforcer was enhanced 30-45% at the most uncertain probabilities. Tolerance did not develop with repeated treatments. Increased discounting subsided within 2 weeks of (±)PPX cessation, and re-exposure to (±)PPX reinstated heightened discounting. Such findings emulate the clinical scenario; therefore, ICSS for discounting assessments in rats exhibited high face validity. This model should prove useful in medication development where assessment of the propensity of a putative therapy to induce risk-taking behaviors is of interest.

Animal models of Parkinson's disease

Parkinson's disease (PD) is a disease of an aging population and its etiology is still unknown. In vivo models are attempts to capture as many of the hallmarks of PD as possible. To this end, a number of animal models are in use. These models parallel our thinking about the etiology of PD. Thus, herein, we discuss the most popular neurotoxin animal models, 6-hydroxydopamine and MPTP as one school of thought believes that PD is the result of a toxic insult. Since several researchers think that pesticide and herbicide use can increase the risk of developing PD, we review some of the aspects of rotenone and paraquat in rodents. Furthermore, now that we know that 10% of all PD cases are genetic in nature, we discuss some of the more common genetic rodent models of PD. None of the above models captures all of the hallmarks of PD. Thus, a given model should never be used indiscriminately to investigate every question, but should instead be carefully selected on the basis of being the most suitable model for the question being asked.

The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu₄), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu₄ PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu₄ in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu₄ PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu₄ PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu₄ PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists.

Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: A self-perpetuating crosstalk?

In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

Automated gait analysis in bilateral Parkinsonian rats and the role of l-DOPA therapy

Gait disturbances and postural instability represent major sources of morbidity in Parkinson's disease (PD), and respond poorly to current treatment options. Some aspects of gait disturbances can be observed in rodent models of PD; however, knowledge regarding the stability of rodent gait patterns over time is lacking. Here we investigated the temporal constancy and reproducibility of gait patterns in neurologically intact and bilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, by using an automated quantitative gait analysis method (CatWalk). The bilateral neurotoxin injections into the medial forebrain bundle resulted in an average dopamine (DA) loss of 70% in each striata, which corresponds to the DA levels observed in moderate-mid stage human PD. Rats were tested weekly during one month, and we found that in intact rats all parameters investigated remained constant over multiple tests. The 6-OHDA lesioned rats were impaired in several aspects of gait, such as stride length, swing speed, stance duration, step cycle duration, and base of support. However the stance and step cycle deficits were transient, the performance of 6-OHDA lesioned rats were indistinguishable from control rats by the last test session with regard to these parameters. Finally, we found that administration of a single dose of levodopa ( l-DOPA) to the 6-OHDA lesioned rats could counteract all but one observed deficits. Based on these findings we conclude that the gait pattern of intact rats is highly reproducible, 6-OHDA lesioned rats display impairments in gait, and l-DOPA can counteract most deficits seen in this model of experimental PD.

High frequency stimulation of the subthalamic nucleus acutely rescues motor deficits and neocortical movement representations following 6-hydroxydopamine administration in rats

Loss of frontal neocortical activation is one of the main neurophysiological abnormalities of Parkinson's disease (PD) and can be observed in rodent models of nigrostriatal degeneration. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus improves motor deficits in PD. However, it is unknown whether this general therapeutic effect is associated with a restoration of frontal output function. To address this question, chronic stimulating electrodes were implanted bilaterally into the subthalamic nuclei of adult rats that received either bilateral intrastriatal 6-hydroxydopamine (6-OHDA) or vehicle infusion to induce nigrostriatal degeneration. Forelimb use and locomotor activity were assessed based on the cylinder and open field tests in intact, post-lesion + sham DBS, and post-lesion + DBS conditions. Intracortical microstimulation was then used to probe frontal output function of forelimb motor areas. DBS was found to improve motor deficits arising from 6-OHDA lesions, increase forelimb map area, and decrease movement thresholds relative to baseline. These effects were significantly greater in 6-OHDA lesion rats compared to vehicle controls. Results indicate that changes in motor map expression can take place during subthalamic DBS following dopamine depletion in a rodent model of PD.

Behavioral and neurophysiological correlates of striatal dopamine depletion: A rodent model of Parkinson's disease

Both limb and cranial motor functions are adversely impacted by Parkinson's disease (PD). While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions. This suggests that the neuropathologies mediating limb and cranial motor impairments in PD may differ. Animal models provide a mechanism by which the potential neural dysfunctions underlying these different motor impairments may be characterized. Central goals to our laboratory have been to (a) determine the differential responses of cranial motor and limb motor function to striatal dopamine depletion and (b) determine the differential effects of striatal dopamine depletion on the integrity of cranial motor and limb motor neural circuits. This paper details the use of a comprehensive battery of limb and cranial motor behavioral tasks and the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits in a rodent model of PD. Our work suggests that striatal dopamine depletion does differentially affect cranial and limb motor function and corticospinal and corticobulbar circuits. Further, we propose that cranial motor impairments in PD may be mediated by pathology both within and outside nigrostriatal dopamine system. Learning outcomes: Readers will be able to (a) describe a set of motor tests used to assess limb motor and cranial motor function in an animal model of Parkinson's disease, (b) understand the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits, (c) describe the differential effects of dopamine depletion on limb motor and cranial motor function in a rodent model of PD, and (d) understand the potential role of dysfunction outside the nigrostriatal system mediating cranial motor impairments in Parkinson's disease.

Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

BackgroundPhosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions.Methodology/Principal FindingsHere we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A.Conclusions/SignificanceOur findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.

Aberrant Dopamine Transmission and Cognitive Dysfunction in Animal Models of Parkinson's Disease

Due to the relative success of therapeutic interventions aimed at treating the overt motor symptoms evident in Parkinson's disease (PD), a greater appreciation of the non-motor aspects of the disease has emerged in recent time. Indeed, evidence suggests that impairments in emotional processing, behavioural control and cognitive function may emerge early in the onset of the disease. Decades of experimental research have seen the development of diverse animal models, all of which have aimed to mimic the characteristic features of the disease process including the dopaminergic neural cell loss, the molecular neuropathology and the concomitant behavioural impairments. The following review provides an overview of the use of animal, particularly rodent, models in the quest to obtain a greater understanding of the role of corticostriatal dopamine in cognitive and neuropsychiatric functions. Given the limitations of using the available rodent models of PD, including altered motor and motivational function, it has become necessary to employ a range of techniques to eke out the precise function of this neurotransmitter in corticostriatal function. Combinations of lesion and pharmacological studies have allowed the assessment of dopamine depletion and precise receptor populations in the learning or expression of a range of executive functions, which has gained us considerable insight into the relationship between the neuropathology that occurs in PD and the resulting impairments in cognitive and neuropsychiatric function.

Cardiovascular Autonomic Dysfunction in Animal Models of Parkinson's Disease

Cardiovascular autonomic dysfunction is a common non-motor symptom associated with synucleinopathies such as Parkinson's disease (PD). Several recent clinical studies indicate that cardiovascular autonomic impairments including orthostatic hypotension and sympathetic denervation may precede the development of the cardinal motor symptoms in PD, making cardiovascular dysfunction an attractive target for the development of biomarkers for early detection and potential neuroprotective strategies for PD. However, the pathologic mechanisms underlying cardiovascular dysfunction as well as many of the non-motor symptoms in PD remain unknown. This is likely due, in part, to an initial under-appreciation of PD as a systemic disorder as well as limited research in cardiovascular dysfunction in animal models of PD. Here, we highlight studies that have investigated cardiovascular dysfunction in rodent models of PD and the potential usefulness of genetic mouse models of PD for this endeavor.

Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

BackgroundCurrent evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg-1 daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP.MethodsAgeing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomial dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP.ResultsHCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in subtantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons.ConclusionsOral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.

POMD09 Understanding the early pathological pathways in Parkinson's disease. The Oxford Parkinson's Disease Centre

The OPDC will focus on understanding the earliest pathological pathways in Parkinson's disease (PD). Scientists with strengths in genetics and genomics, transgenic rodent PD models, in vivo neuroanatomy and neuropharmacology...

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague–Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.

LINGO1 is not associated with Parkinson's disease in German patients

Essential tremor (ET) and Parkinson's disease (PD) are the most common movement disorders and show clinical, genetic, and pathophysiological overlap. Single-nucleotide polymorphisms (SNPs) in the leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein gene (LINGO1) are associated with ET. LINGO1 is overexpressed in the substantia nigra (SN) of PD patients and inhibition of LINGO1 confers neuroprotection in a rodent model of PD. In this study we test the hypothesis whether SNPs in the LINGO1 gene that are associated with ET are also associated with PD. Three large German case-control samples from Kiel, Lübeck, and Tübingen (total: 1,798 cases and 1,482 controls) were genotyped for the three LINGO1 SNPs associated with ET. Association was assessed using allele- and genotype-based tests in each of the three samples separately, in the combined sample, and in subsets of patients with early-onset PD (<50 years) and of patients with a positive family history of PD. Neither of the three samples alone nor the combined sample showed evidence for association between LINGO1 SNPs and PD. The allele-based test showed a trend toward nominal association for all three SNPs in the Kiel sample. The subsets with early-onset PD or a positive family history did also not reveal evidence for association. SNPs in the LINGO1 gene associated with ET could not be shown to be associated with PD in our study population, despite a postulated overlap between both diseases.

Preladenant, a selective A 2A receptor antagonist, is active in primate models of movement disorders

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D 2 receptors by antipsychotics, respectively. Adenosine A 2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal (“indirect”) pathway, where they appear to operate in concert with D 2 receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A 2A receptor activation contributes to the overdrive of the indirect pathway. A 2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A 2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A 2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A 2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3–3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.

Paeoniflorin, a potent natural compound, protects PC12 cells from MPP + and acidic damage via autophagic pathway

Ethnopharmacological relevance Paeoniflorin (PF) is the principal bioactive component of Radix Paeoniae alba, which is widely used in Traditional Chinese Medicine for the treatment of neurodegenerative disorders such as Parkinson's disease (PD). Aim of the study To evaluate the neuroprotective effects of PF on MPP +- or acid- (pH 5.0) induced injury in cultured PC12 cells and to investigate the activity of autophagy-lysosome pathway (ALP). Amiloride (Ami), a non-selective blocker of acid-sensing ion channels (ASICs), as a positive control drug, since it is neuroprotective in rodent models of PD. Materials and methods The cell viability was analyzed with MTT assay. The cell injury was assessed by lactate dehydrogenase (LDH) assay. Flow cytometry and Western blot analysis were used to study the apoptotic, calcium influx and autophagic mechanisms. Results Ami (100 μM) and PF (50 μM) both protected PC12 cells against MPP +- or acid-induced injury as assessed by MTT assay, lactate dehydrogenase release, and apoptosis rate. The concentrations of cytosolic free Ca 2+ were raised after exposure to MPP + or acidosis, while Ami and PF both reduced the influx of Ca 2+. More importantly, we found that the mechanisms of neuroprotective effects of Ami and PF were closely associated with the upregulation of LC3-II protein, which is specifically associated with autophagic vacuole membranes. Furthermore, application of MPP + or acid induced the overexpression of LAMP2a, which is directly correlated with the activity of the chaperone-mediated autophagy pathway. However, Ami and PF inhibited the overexpression of LAMP2a. Conclusions Our data provide the first experimental evidence that PF modulates autophagy in models of neuron injury, as well as providing the first indication of a relationship between ASICs and ALP.

643 Degradation of C/EBPalpha by Trib proteins correlates with Trib mediated acute myeloid leukemia

Using traditional linkage analysis and positional cloning, mutations in genes encoding PARKIN, PINK1, and DJ-1 have been causally associated with the autosomal recessive Parkinson disease (PD) variants PARK2, PARK6, and PARK7, respectively. Traditional germline knock-out models targeting PARKIN, PINK1, and DJ-1 have failed to recapitulate the preferential affection of the substantia nigra pars compacta by core features of late-stage PD, particularly the formation of classical Lewy body and Lewy neurite protein aggregates and the selective loss of dopaminergic neurons, which result in the classical phenotype of deficient spontaneous locomotion in PD. However, in vivo and in vitro studies using knock-out, knock-down, and overexpression have shown a role for these proteins in stress-response and quality-control, particularly in the autophagic degradation of dysfunctional mitochondria as a crucial pathobiological feature of Parkinsonism. Although face validity has been limited to date, rodent PD models are improving, by combining stressors with the absence of stress-response, by using conditional knock-outs, and by overexpressing dominant-negative factors. Rodent models will be crucial to understand the cell-type specific neurodegeneration in PD and to identify disease preventative treatments that target central pathogenic processes rather than providing only symptomatic benefit. In this chapter, we review rodent models for three recessive forms of PD and a variety of multiplex mutants that have yielded important insights into the altered biology of mitochondria in PD.

Transplantation of Undifferentiated Human Mesenchymal Stem Cells Protects against 6-Hydroxydopamine Neurotoxicity in the Rat

Stem cells have been increasingly recognized as a potential tool to replace or support cells damaged by the neurodegenerative process that underlies Parkinson's disease (PD). In this frame, human adult mesenchymal stem cells (hMSCs) have been proposed as an attractive alternative to heterologous embryonic or neural precursor cells. To address this issue, in this study we implanted undifferentiated hMSCs into the striatum of rats bearing a lesion of the nigrostriatal pathway induced by local injection of 6-hydroxydopamine (6-OHDA), a widely recognized rodent model of PD. Before grafting, cultured hMSCs expressed markers of both undifferentiated and committed neural cells, including nestin, GAP-43, NSE, beta-tubulin III, and MAP-2, as well as several cytokine mRNAs. No glial or specific neuronal markers were detected. Following transplantation, some hMSCs acquired a glial-like phenotype, as shown by immunoreactivity for glial fibrillary acid protein (GFAP), but only in animals bearing the nigrostriatal lesion. More importantly, rats that received the striatal graft showed increased survival of both cell bodies and terminals of dopaminergic, nigrostriatal neurons, coupled with a reduction of the behavioral abnormalities (apomorphine-induced turning behavior) associated with the lesion. No differentiation of the MSCs toward a neuronal (dopaminergic) phenotype was observed in vivo. In conclusion, our results suggest that grafted hMSCs exert neuroprotective effects against nigrostriatal degeneration induced by 6-OHDA. The mechanisms underlying this effect remain to be clarified, although it is likely that the acquisition of a glial phenotype by grafted hMSCs may lead to the release of prosurvival cytokines within the lesioned striatum.

Parkinsonian brain activity patterns in urethane-anesthetized VMAT2-deficient mice

Event Abstract Back to Event Parkinsonian brain activity patterns in urethane-anesthetized VMAT2-deficient mice Jeremy R. Edgerton1* and Dieter Jaeger1 1 Emory University, Faculty of Electrical Engineering and Computing, United States Parkinson's disease (PD) is a devastating neurological disorder involving the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). SNc neurons project principally to the striatum and other regions of the basal ganglia, and the loss of dopaminergic modulation in this circuit results in akinesia, rigidity and tremor - the movement symptoms that are the hallmarks of PD. In addition to the motor symptoms of PD, there are a number of non-motor symptoms that typically do not respond as well to dopamine replacement therapy. It has been proposed that these non-motor symptoms may involve the noradrenergic and serotonergic neurotransmitter systems, which also show significant degeneration in PD. In support of this hypothesis, a recent study found that mice expressing only 5% of the normal level of the vesicular monoamine transporter 2 (VMAT2 LO mice), resulting in severely depleted levels of DA, NE and 5-HT, display both an age-dependent motor phenotype and several of the non-motor symptoms of PD [1]. Neurophysiological studies of dopamine-depleted primate and rodent models of PD have found altered neuronal firing rates and patterns at multiple basal ganglia sites including the output nuclei. Three pattern changes have been emphasized as consistent features of Parkinsonian brain activity: increased burst firing, abnormal 8 - 45 Hz oscillations, and elevated synchrony between neurons. To determine the neurophysiological correlates of the Parkinsonian phenotype observed in VMAT2 LO mice, we have compared local field potential and single-unit activity between these mice and wild-type controls. We recorded simultaneously from three brain regions: the substantia nigra pars reticulata (SNr), which is a major basal ganglia output nucleus composed of GABAergic projection neurons; the ventral medial thalamus (VM), which is one of the principal targets of the SNr in mice; and motor cortex, which is reciprocally connected with VM and also a major source of input to the basal ganglia circuit. Preliminary results show markedly increased oscillatory power at about 10 Hz in the VMAT2 LO mice under urethane anesthesia. The 10 Hz oscillations were highly coherent between motor cortex, SNr and VM, consistent with increased synchrony across the cortico-basal ganglia network. The elevated oscillations were not observed under isoflurane anesthesia, and were observed under urethane only during periods of cortical activation induced by a toe-pinch stimulus. These results indicate that VMAT2 LO mice show some of the same neuronal activity pattern abnormalities that are characteristic of more established animal models of PD.

How useful are stem cells in PD therapy?

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The onset of PD is usually after the age of 50. Clinical symptoms of PD are not manifested until 60-80% of dopaminergic neurons in the midbrain have been affected. Cell replacement has been a promising approach for the treatment of PD. Fetal mesencephalic dopaminergic neurons seemed to improve the motor disability in patients in some early studies. However, the clinical application of this approach may be limited by ethical and logistic concerns, as well as by side effects. On the other hand, embryonic stem (ES) cells are promising candidates because of their ability to provide an unlimited supply of specific cell types, their accessibility to genetic modifications, and their broad developmental potentials. Transplants of undifferentiated ES cells were able to proliferate and fully differentiate into dopaminergic neurons in a rodent PD model. One of the concerns though is the risk of tumor formation. The tumorigenic potential of ES cells seems to be greatly reduced when cells are predifferentiated into dopaminergic neurons in vitro before implantation. Recent developments in the induction of pluripotent stem cells from somatic adult cells provide a tremendous opportunity for this field. Initial success has been reported in a rodent PD model using iPS cells (induced pluripotent stem cells). However, whether this initial result can be successfully translated into human clinical studies still needs to be determined.