Future Treatments for Parkinson's Disease: Surfing the PD Pipeline

Department of Neurology, College of Medicine, University of South Florida, Tampa, Florida 33606, USA.
The International journal of neuroscience (Impact Factor: 1.52). 09/2011; 121 Suppl 2(S2):53-62. DOI: 10.3109/00207454.2011.620195
Source: PubMed

ABSTRACT Our current wish list for the treatment of Parkinson's disease (PD) includes therapies that will provide robust and sustained antiparkinsonian benefit through the day, ameliorate or prevent dyskinesia, and slow or prevent the progression of the disease. In this article, I review selected new therapies in clinical development for motor features or treatment complications of PD, and some that may slow disease progression. These include adenosine 2a (A2a) antagonists (istradefylline, preladenant, and SYN115), levodopa/carbidopa intestinal gel (LCIG), IPX066--an extended-release formulation of carbidopa/levodopa, XP21279--a sustained-release levodopa prodrug, ND0611--a carbidopa subcutaneous patch, safinamide--a mixed mechanism of action medication that may provide both MAO-B and glutamate inhibition, PMY50028--an oral neurotrophic factor inducer, antidyskinesia medications (AFQ056 and fipamezole), and gene therapies (AAV2-neurturin and glutamic acid decarboxylase gene transfer). Some of these therapies will never be proven efficacious and will not come to market while others may play a key role in the future treatment of PD.

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Available from: Robert A Hauser, Nov 07, 2014
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    • "Given alone the drug has no anti-symptomatic action, and together with L-DOPA it reduced off-time, the time in a day when the medication is not working properly, in the order of 1 h (Poewe et al., 2012). As phase III clinical trials showed no significant reduction in off time in comparison to L-DOPA treatment, the drug was not approved by the USA Federal Drug Administration (Hauser, 2011). By contrast, istradefylline was approved for use in Japan for treatment of PD as an enhancer of L-DOPA actions, especially of the wearing-off phenomena (Dungo and Deeks, 2013), with the trade name Nouriast ® (20 mg tablets). "
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    ABSTRACT: Purinergic signaling modulates dopaminergic neurotransmission in health and disease. Classically adenosine A1 and A2A receptors have been considered key for the fine tune control of dopamine actions in the striatum, the main CNS motor control center. The main adenosine signaling mechanism is via the cAMP pathway but the future will tell whether calcium signaling is relevant in adenosinergic control of striatal function. Very relevant is the recent approval in Japan of the adenosine A2A receptor antagonist, istradefylline, for use in Parkinson's disease patients. Purine nucleotides are also regulators of striatal dopamine neurotransmission via P2 purinergic receptors. In parallel to the alpha-synuclein hypothesis of Parkinson's disease etiology, purinergic P2X1 receptors have been identified as mediators of accumulation of the Lewy-body enriched protein alpha-synuclein. Of note is the expression in striatum of purinergic-receptor-containing heteromers that are potential targets of anti-Parkinson's disease therapies and should be taken into account in drug discovery programs. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 07/2015; DOI:10.1016/j.neuropharm.2015.07.024 · 5.11 Impact Factor
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    • "For example, a recent methodology using magnetic nanocarriers for the transport of BDNF was able to cross the BBB without affecting cell viability seems promising (Pilakka-Kanthikeel et al., 2013). A different approach seems to be the transplantation of dopaminergic neurons or glial precursor cells into the injured regions of the brain, which increases the expression of growth factors like BDNF, GDNF, and IGF (Hauser, 2011; Jankovic and Poewe, 2012; Proschel et al., 2014). In this aspect, a recent study by Proschel et al. (2014) has demonstrated that the transplantation of glial precursor cells in 6-OHDA injured rats causes the recovery of DA neurons of the striatum by an increase in the levels of GSH, GDNF, and BDNF. "
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    ABSTRACT: The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.
    Frontiers in Cellular Neuroscience 08/2014; 8. DOI:10.3389/fncel.2014.00211 · 4.29 Impact Factor
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    • "Regarding Parkinson's disease, our knowledge is still limited to the mechanism of damage to the dopaminergic system in the central nervous system. Therefore, the drug design strategy currently valid for treating this disease is the activation of dopamine receptors to compensate for the lacked dopaminergic neurons [83] . It is expected that the market for drugs treating Parkinson's disease will continue to increase in the near future [84] . "
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    ABSTRACT: In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson's disease, and on muscarinic receptors for Alzheimer's disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson's disease. Regarding the treatment of Alzheimer's disease, the design of dualsteric ligands for mono-oligomeric rinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
    Neural Regeneration Research 08/2013; 8(24):2290-302. DOI:10.3969/j.issn.1673-5374.2013.24.009 · 0.22 Impact Factor
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