Advances in non-dopaminergic treatments for Parkinson's disease

Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable. © 2014 Stayte and Vissel

Activin a protects midbrain neurons in the 6-hydroxydopamine mouse model of Parkinson's disease

© 2015 Stayte et al. Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor β superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naive mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain

Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia.

L-dopa induced dyskinesia (LID) is a debilitating side-effect of the primary treatment used in Parkinson's disease (PD), l-dopa. Here we investigate the effect of HU-308, a cannabinoid CB2 receptor agonist, on LIDs. Utilizing a mouse model of PD and LIDs, induced by 6-OHDA and subsequent l-dopa treatment, we show that HU-308 reduced LIDs as effectively as amantadine, the current frontline treatment. Furthermore, treatment with HU-308 plus amantadine resulted in a greater anti-dyskinetic effect than maximally achieved with HU-308 alone, potentially suggesting a synergistic effect of these two treatments. Lastly, we demonstrated that treatment with HU-308 and amantadine either alone, or in combination, decreased striatal neuroinflammation, a mechanism which has been suggested to contribute to LIDs. Taken together, our results suggest pharmacological treatments with CB2 agonists merit further investigation as therapies for LIDs in PD patients. Furthermore, since CB2 receptors are thought to be primarily expressed on, and signal through, glia, our data provide weight to suggestion that neuroinflammation, or more specifically, altered glial function, plays a role in development of LIDs

Parafascicular Thalamic and Orbitofrontal Cortical Inputs to Striatum Represent States for Goal-Directed Action Selection

Several lines of evidence accrued over the last 5-10 years have converged to suggest that the parafascicular nucleus of the thalamus and the lateral orbitofrontal cortex each represent or contribute to internal state/context representations that guide action selection in partially observable task situations. In rodents, inactivations of each structure have been found to selectively impair performance in paradigms testing goal-directed action selection, but only when that action selection relies on state representations. Electrophysiological evidence has suggested that each structure achieves this function via inputs onto cholinergic interneurons (CINs) in the dorsomedial striatum. Here, we briefly review these studies, then point to anatomical evidence regarding the afferents of each structure and what they suggest about the specific features that each contribute to internal state representations. Finally, we speculate as to whether this role might be achieved interdependently through direct PF→OFC projections, or through the convergence of independent direct orbitofrontal cortex (OFC) and parafascicular nucleus of the thalamus (PF) inputs onto striatal targets

General Anaesthetic Modulation of Memory-Related Gene Expression Using an In vitro Brain Slice Model

General anaesthetics cause widespread neurochemical and physiological changes in the brain. However, the precise mechanism of amnesic action is largely unknown. Gene expression changes in the hippocampus have been a focal point for investigation in this area, while effects on the cerebral cortex have been largely underreported even though the cerebral cortex has been shown to play a large role in memory consolidation and storage. Amnesia is likely due to the change in expression of memory-related genes within the neocortex or hippocampus of the mammalian brain. The first aim of this research was to investigate the in vitro cortical gene expression pattern of two memory-related genes; activity-regulated cytoskeleton-associated protein (Arc) and brain-derived neurotrophic factor (Bdnf), after a t=4 hour exposure to propofol- or sevoflurane- induced anaesthesia using an adult mouse brain slice model and real-time quantitative PCR. Five animals were used for each anaesthetic and a t=0 hour control, t=4 hour control and t=4 hour treated 400 μm slice were taken from each animal. Seizure-like activity was recorded from the brain slices to ensure viability of the tissue before carrying out the anaesthetic exposure. RNA was extracted, DNAse-treated, and then converted to cDNA. Quantitative PCR was then carried out to analyse Bdnf and Arc expression differences between the t=4 hour control and t=4 hour treated samples using Gapdh, β2m, Actb and HRPT1 as reference genes. The second research aim was to determine the Bdnf protein expression level and localisation after a t=4 hour exposure to propofol using western blot and immunohistochemistry methodologies. Our research demonstrated that Arc was significantly down-regulated after exposure to sevoflurane for t=4 hours (p<0.05). Arc was also shown to be up-regulated after a t=4 hour exposure to propofol while Bdnf showed a downregulation to sevoflurane but an upregulation to propofol, however this data was not statistically significant. Western blot data showed that the rabbit polyclonal Bdnf antibody was binding to an off-target epitope at 55 kDa with mouse brain, heart, lung, liver, spleen and kidney whole tissue lysate. A newly sourced commercial Bdnf antibody was validated and western blot data showed recognition of the Bdnf epitope at the correct predicted size of 28 kDa in the mouse brain, heart and kidney. Immunohistochemistry of frozen mouse brain sections failed to produce a positive signal for two different Bdnf antibodies due to encountering technical issues. Hematoxylin and Eosin staining showed the tissue was still intact after the sectioning procedure. These issues could be resolved in the future by improving the tissue fixation length and optimising the antigen retrieval step. Eleven recommendations have been made to provide further insight into the gene expression levels of memory-related genes in the mouse brain. This includes varying the induction and maintenance of the two anaesthetic drugs, role of epigenetic modification, evaluating the mental state of the mice (depression), investigating Bdnf knockout, differential expression between areas of the brain and brain electrical activity. In addition, the gene expression pattern after a period of anaesthetic exposure should also be analysed. This may help elucidate the causes of postoperative cognitive dysfunction. Whole transcriptome analysis using RNA-Seq could be used to determine the expression levels of other known memory-related genes after anaesthetic exposure

Activin A inhibits MPTP and LPS-induced increases in inflammatory cell populations and loss of dopamine neurons in the mouse midbrain in Vivo

© 2017 Stayte et al. Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease

The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain

© 2019 Elsevier Inc. The excitatory neurotransmitter glutamate is essential in basal ganglia motor circuits and has long been thought to contribute to cell death and degeneration in Parkinson's disease (PD). While previous research has shown a significant role of NMDA and AMPA receptors in both excitotoxicity and PD, the third class of ionotropic glutamate receptors, kainate receptors, have been less well studied. Given the expression of kainate receptor subunits GluK1-GluK3 in key PD-related brain regions, it has been suggested that GluK1-GluK3 may contribute to excitotoxic cell loss. Therefore the neuroprotective potential of the kainate receptor antagonist UBP310 in animal models of PD was investigated in this study. Stereological quantification revealed administration of UBP310 significantly increased survival of dopaminergic and total neuron populations in the substantia nigra pars compacta in the acute MPTP mouse model of PD. In contrast, UBP310 was unable to rescue MPTP-induced loss of dopamine levels or dopamine transporter expression in the striatum. Furthermore, deletion of GluK1, GluK2 or GluK3 had no effect on MPTP or UBP310-mediated effects across all measures. Interestingly, UBP310 did not attenuate cell loss in the midbrain induced by intrastriatal 6-OHDA toxicity. These results indicate UBP310 provides neuroprotection in the midbrain against MPTP neurotoxicity that is not dependent on specific kainate receptor subunits

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus (ICN) is characterised by involuntary, periodic, predominantly horizontal, oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 ICN singleton cases (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina suggesting a specific role in the control of eye movement and gaze stability