Neuroprotection in Parkinson models varies with toxin administration protocol

Numerous factors contribute to substantia nigra pars compacta (SNc) dopamine (DA) neuron death in Parkinson's disease (PD), thus complicating the search for effective neuroprotective agents for this disease. Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse has been widely used for assessing neuroprotective agents for PD, the pathological processes resulting from MPTP exposure can vary greatly depending upon the MPTP administration protocol. This study assessed the degree to which the neuroprotective efficacy of particular agents may depend upon the MPTP administration protocol (i.e. acute vs. subacute toxin administration). Endpoints analysed were changes in tyrosine hydroxylase (TH) and NeuN cell numbers in the SNc, striatal DA and metabolite levels, and striatal TH+ fiber density. The efficacy of putative neuroprotective agents [i.e. LIGA 20, nicotinamide and pramipexole (PPX)] varied depending upon the MPTP administration protocol. LIGA 20 spared striatal DA levels in both MPTP models, while nicotinamide was only effective in the acute toxin administration model and PPX was only effective in the subacute model. In both MPTP models, LIGA 20 and nicotinamide significantly spared DAergic neurons; PPX only spared DAergic neurons in the subacute model. Only acute MPTP-treated mice that received nicotinamide had a significant sparing of striatal DAergic fibers. These results underscore the need to assess putative neuroprotective agents for PD in multiple animal models using multiple endpoints. This strategy may better identify compounds with broad neuroprotective/neurorestorative profiles that may be more likely to be clinically effective.     

SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta

Parkinson's disease (PD) is characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). It is widely believed that replacing lost SNc DA neurons is a key to longer-term effective treatment of PD motor symptoms, but generating new SNc DA neurons in PD patients has proven difficult. Following loss of tyrosine hydroxylase-positive (TH+) SNc neurons in the rodent 6-hydroxy-DA (6-OHDA) model of PD, the number of TH+ neurons partially recovers and there is evidence this occurs via phenotype “shift” from TH− to TH+ cells. Understanding how this putative phenotype shift occurs may help increase SNc DAergic neurons in PD patients. In this study we characterize the electrophysiology of SNc TH− and TH+ cells during recovery from 6-OHDA in mice. Three distinct phenotypes were observed: (1) TH− were fast discharging with a short duration action potential (AP), short afterhyperpolarization (AHP) and no small conductance Ca²⁺-activated K⁺ (SK) current; (2) TH+ were slow discharging with a long AP, long AHP and prominent SK current; and (3) cells with features “intermediate” between these TH− and TH+ phenotypes. The same 3 phenotypes were present also in the normal and D2 DA receptor knock-out SNc suggesting they are more closely related to the biology of TH expression than recovery from 6-OHDA. Acute inhibition of SK channel function shifted the electrophysiological phenotype of TH+ neurons toward TH− and chronic (2 weeks) inhibition of SK channel function in normal mice shifted the neurochemical phenotype of SNc from TH+ to TH− (i.e. decreased TH+ and increased TH− cell numbers). Importantly, chronic facilitation of SK channel function shifted the neurochemical phenotype of SNc from TH− to TH+ (i.e. increased TH+ and decreased TH− cell numbers). We conclude that SK channel function bidirectionally regulates the DA phenotype of SNc cells and facilitation of SK channels may be a novel way to increase the number of SNc DAergic neurons in PD patients.     

Dopaminergic neurons expressing calbindin in normal and parkinsonian monkeys.

In cynomolgus monkeys, midbrain neurons immunoreactive (IR) for the calcium-binding protein calbindin D-28k (CaBP) occur principally in the dorsal tier of substantia nigra pars compacta (SNc) and in the ventral tegmental area (VTA), and most of these neurons co-express tyrosine hydroxylase (TH). In monkeys rendered parkinsonian (PD) after MPTP injections, CaBP-IR neurons are much less severely affected than TH-IR neurons in SNc and in VTA, and most spared neurons in SNc/VTA display both CaBP and TH immunoreactivity. These results reveal that, in contrast to the situation in other neurodegenerative diseases, CaBP may be used as a marker for a specific neuronal population that is less prone to degeneration in Parkinson's disease.     

The role of synphilin-1 in the pathogenesis of Parkinson＇s disease

Parkinson＇s disease （PD） is one of the commonest neurodegenerative disorders characterized by the loss of dopaminergic （DAergic） neurons in the substantia nigra and the appearance of Lewy bodies （LBs）, whose cytoplasmic inclusions are highly enriched with ubiquitin, synphilin- 1, α-synuclein and park：in. Synphilin- 1 is an α-synuclein-binding protein and a major component of LBs, It is widely accepted that synphilin- 1 is involved in the pathogenic process of PD. This review will provide an overall view of the role of synphilin- 1 in the pathogenesis of Parkinson＇ s disease and the latest findings in this field.     

Oxidative stress and inflammation in Parkinson's disease: is there a causal link?

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.     

The involvement of NF-kappaB p65/p52 in the effects of GDNF on DA neurons in early PD rats

Glial cell line-derived neurotrophic factor (GDNF) can exert neuroprotective effects on the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons that are undergoing degeneration in Parkinson's disease (PD). In an attempt to investigate the molecular signaling mechanisms underlying GDNF protection the DA neurons from degeneration, we established early PD rat models in which the DA neurons in SNc were degenerating. Whether the cytoplasmic NF-κB signaling pathway was involved in the protection of GDNF on the degenerating DA neurons was examined in the present study. The results showed that the nuclear NF-κB p65 levels in the DA neurons increased when GDNF was injected into SNc of early PD rat models. Immunoprecipitation assays showed that the nuclear NF-κB p65/p52 complex levels increased after GDNF administration, while the p65/p50 complex levels decreased. These results indicated that GDNF could activate the NF-κB signaling pathway in the degenerating DA neurons. And it was the noncanonical NF-κB signaling pathway, which contained the NF-κB p65/p52 complex that was involved in the effects of GDNF on DA neurons.     

Altered proteasomal function in sporadic Parkinson's disease

Parkinson's disease (PD) is characterized pathologically by preferential degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). Nigral cell death is accompanied by the accumulation of a wide range of poorly degraded proteins and the formation of proteinaceous inclusions (Lewy bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are associated with neurodegeneration in some familial forms of PD. We now show that, in comparison to age-matched controls, alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the SNc in sporadic PD. In addition, while the levels of the PA700 proteasome activator are reduced in the SNc in PD, PA700 expression is increased in other brain regions such as the frontal cortex and striatum. We also found that levels of the PA28 proteasome activator are very low to almost undetectable in the SNc compared to other brain areas in both normal and PD subjects. These findings suggest that failure of the ubiquitin-proteasome system to adequately clear unwanted proteins may underlie vulnerability and degeneration of the SNc in both sporadic and familial PD.     

Lesion of substantia nigra pars compacta by the GluR5 agonist ATPA

Dopamine (DA) released by substantia nigra pars compacta (SNc) neurons is a key regulator of motor activity. A deficiency in the striatum DA content due to SNc degeneration is a characteristic of Parkinson's disease. The involvement of excitotoxic mechanisms in this pathology has been suggested. The kainate receptor subunit GluR5 has been identified in a few basal ganglia but it is strongly expressed in SNc. Here we examine whether (RS)-2-amino-3-(3-hydroxy-5-tbutylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist of GluR5, induces damage in dopaminergic (DAergic) neurons. ATPA (13 nmol) was administered to rat SNc. Immediately after recovery from surgery, the rats displayed ipsilateral turning. This behavior disappeared in subsequent days. The administration of the D1/D2 agonist, apomorphine (1 mg/kg, s.c.) 1 and 2 weeks after ATPA-infusion also induced ipsilateral turning. Histological studies-performed 21 days after ATPA-infusion-showed a lesion of the lateral and central part of the SNc, where a significant loss (36%) of DAergic cells was detected by tyrosine hydroxylase immunohistochemistry. The lesion was restricted to the SNc, since no damage or glial reaction was observed in the substantia nigra pars reticulata as assessed by Nissl staining, tomato lectin staining for microglial cells and GFAP immunohistochemistry for astrocytes. In conclusion: (1). ATPA-infusion induces neuronal damage in the SNc in the rat and (2). the behavioral effects of unilateral infusion of ATPA are consistent with DAergic alterations in basal ganglia.     

NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-OHDA rat model of Parkinson''s disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.     

Parkinson's disease and related synucleinopathies are a new class of nervous system amyloidoses

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. While the classic clinical-neuropathological features of PD have been well established, mechanisms underlying brain degeneration in PD are unknown, and only partially effective symptomatic treatments for PD exist. Further, there are no therapeutic interventions that prevent PD or block the progression of this relentless neurodegenerative disorder. However, dramatic new insights into the role of alpha-synuclein (AS) in the pathobiology of PD have emerged recently, and this has led to the development of transgenic animal models of PD-like AS pathologies. Continuing advances in this research direction should advance understanding of PD and accelerate discovery of more effective therapies for this and related synucleinopathies.