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Cellular and Molecular Neurobiology Aug 2023Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and... (Review)
Review
Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.
Topics: Humans; Parkinson Disease; Hyperhomocysteinemia; Levodopa; Substantia Nigra; Neurodegenerative Diseases; Dopaminergic Neurons
PubMed: 37074484
DOI: 10.1007/s10571-023-01350-8 -
The Journal of Physiology Oct 2021In newborn rats, L-DOPA increases the occurrence of air-stepping activity without affecting movement characteristics. L-DOPA administration increases the spinal content...
KEY POINTS
In newborn rats, L-DOPA increases the occurrence of air-stepping activity without affecting movement characteristics. L-DOPA administration increases the spinal content of dopamine in a dose-dependent manner. Injection of 5-HTP increases the spinal serotonin content but does not trigger air-stepping. 5-HTP counteracts the pro-locomotor action of L-DOPA. Less dopamine and serotonin are synthesized when L-DOPA and 5-HTP are administered as a cocktail.
ABSTRACT
The catecholamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is a well-established pharmacological agent for promoting locomotor action in vertebrates, including triggering air-stepping activities in the neonatal rat. Serotonin is also a well-known neuromodulator of the rodent spinal locomotor networks. Here, using kinematic analysis, we compared locomotor-related activities expressed by newborn rats in response to varying doses of L-DOPA and the serotonin precursor 5-hydroxytryptophan (5-HTP) administered separately or in combination. L-DOPA alone triggered episodes of air-stepping in a dose-dependent manner (25-100 mg/kg), notably determining the duration of locomotor episodes, but without affecting step cycle frequency or amplitude. In contrast, 5-HTP (25-150 mg/kg) was ineffective in instigating air-stepping, but altered episode durations of L-DOPA-induced air-stepping, and decreased locomotor cycle frequency. High performance liquid chromatography revealed that L-DOPA, which was undetectable in control conditions, accumulated in a dose-dependent manner in the lumbar spinal cord 30 min after its administration. This was paralleled by an increase in dopamine levels, whereas the spinal content of noradrenaline and serotonin remained unaffected. In the same way, the spinal levels of serotonin increased in parallel with the dose of 5-HTP without affecting the levels of dopamine and noradrenaline. When both precursors are administrated, they counteract each other for the production of serotonin and dopamine. Our data thus indicate for the first time that both L-DOPA and 5-HTP exert opposing neuromodulatory actions on air-stepping behaviour in the developing rat, and we speculate that competition for the production of dopamine and serotonin occurs when they are administered as a cocktail.
Topics: 5-Hydroxytryptophan; Animals; Animals, Newborn; Dopamine; Levodopa; Rats; Serotonin
PubMed: 34411301
DOI: 10.1113/JP281983 -
Advances in Experimental Medicine and... 2023The need for new drugs to treat dry forms of age-related macular degeneration remains high. A promising approach is repurposing of FDA-approved medications to treat AMD....
The need for new drugs to treat dry forms of age-related macular degeneration remains high. A promising approach is repurposing of FDA-approved medications to treat AMD. Databases containing medical and drug records allow for retroactive identification of drugs whose use correlates with reduced AMD diagnosis. This short review summarizes progress in several classes of drugs considered for repurposing: GPR-143 agonists (L-DOPA), anti-diabetic drugs (metformin, acarbose, empagliflozin, fenofibrate), mitochondrial activators (PU-91), and serotonin pathway drugs (fluoxetine, flibanserin, xaliproden, buspirone). The promises and caveats of repurposing are discussed herein.
Topics: Humans; Drug Repositioning; Macular Degeneration; Levodopa; Metformin
PubMed: 37440017
DOI: 10.1007/978-3-031-27681-1_12 -
Expert Review of Neurotherapeutics Jul 2019: For patients with Parkinson's disease (PD), the treatment of motor and nonmotor fluctuations is tantamount to maintaining quality of life. Subcutaneous apomorphine has... (Review)
Review
: For patients with Parkinson's disease (PD), the treatment of motor and nonmotor fluctuations is tantamount to maintaining quality of life. Subcutaneous apomorphine has been the only commercially available rescue therapy for the treatment of OFF episodes. In December 2018, CVT-301 (Inbrija), an inhaled formulation of levodopa (LD), was approved by the FDA for this indication. : In this review, the authors summarize the armamentarium available to address motor fluctuations in PD, including medications in development. The authors discuss the pharmacological properties of CVT-301 as well as its efficacy and safety as reported in phase I, II, and III studies. : More than 20 medications or surgical procedures are available or in development to address motor fluctuations in PD. Deep brain stimulation (DBS) is an invasive but effective intervention at the end of the treatment spectrum. Less invasive therapies are used in combination to ameliorate motor fluctuations. Rescue therapies can help patients taking oral medications who experience delayed onset symptom relief (delayed ON), and unexpected wearing OFF by providing rapid and durable symptoms relief. CVT-301, an inhaled LD formulation, provides a safe and effective delivery mechanism that may be preferred by patients over subcutaneous injections.
Topics: Administration, Inhalation; Antiparkinson Agents; Humans; Levodopa; Parkinson Disease; Quality of Life
PubMed: 31104518
DOI: 10.1080/14737175.2019.1621748 -
Biochimica Et Biophysica Acta Sep 2016Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible... (Review)
Review
BACKGROUND
Dopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive.
SCOPE OF REVIEW
Prolong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease.
CONCLUSION
Hyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease.
GENERAL SIGNIFICANCE
This review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency.
Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain; Dopamine; Humans; Hyperhomocysteinemia; Levodopa; Parkinson Disease
PubMed: 27318154
DOI: 10.1016/j.bbagen.2016.06.018 -
Journal of Pharmacological Sciences Jul 2023Methylphenidate (MPH) and methamphetamine (METH) are the current treatments of choice for attention deficit/hyperactivity disorder. We previously reported that METH...
Methylphenidate (MPH) and methamphetamine (METH) are the current treatments of choice for attention deficit/hyperactivity disorder. We previously reported that METH induces the release of dopamine (DA) and of the neurotransmitter candidate L-3,4-dihydroxyphenylalanine (L-DOPA). In contrast, we here found that MPH increased the DA release while it did not affect the L-DOPA release from the dorsolateral striatum. Nevertheless, MPH-induced hyperlocomotion was reduced in Gpr143 (L-DOPA receptor) gene-deficient (Gpr143) mice. The rewarding effect and increased c-fos expression induced by MPH were also attenuated in Gpr143 mice. Together, these findings suggest that GPR143 is involved in the acute and chronic actions of MPH.
Topics: Mice; Animals; Methylphenidate; Levodopa; Receptors, Neurotransmitter; Dopamine; Methamphetamine; Central Nervous System Stimulants
PubMed: 37257945
DOI: 10.1016/j.jphs.2023.04.006 -
Journal of Neural Transmission (Vienna,... Nov 2023Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in... (Review)
Review
Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in characteristic symptoms in experimental studies and could be antagonized by DOPA (3,4-dihydroxyphenylalanin), suggesting a similarity to the human disorder Parkinson´s disease (PD) and a therapeutic potential which was successfully exploited from the 1970s on. This was due to the pioneering work of Arvid Carlsson and clinicians around the world who first worked on the breakthrough of L-DOPA therapy and then on its amendment and modification and on alternative therapies for PD patients. All these developments led to the establishment of PD therapy as we know it today. It is characterized by the availability of many different compounds which are mostly employed in combination and by different methods: orally, intravenously, transdermally, subcutaneously, or duodenally. Here, we present without claim of completeness some personal reflections about causal drug developments for PD patients and reflect on some personal interactions with leading clinicians and basic researchers who cooperated with us. Such interactions are crucial for the creation, sometimes serendipitously, of fresh ideas and to further develop existing concepts to make therapeutical progress.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Berlin; Dopamine
PubMed: 37796288
DOI: 10.1007/s00702-023-02692-9 -
EBioMedicine Sep 2017
Topics: Brain; Glucagon-Like Peptide-1 Receptor; Humans; Levodopa; Mitochondria; Parkinson Disease; T-Lymphocytes, Cytotoxic; alpha-Synuclein
PubMed: 28919144
DOI: 10.1016/j.ebiom.2017.09.009 -
Journal of Neural Transmission (Vienna,... Nov 2023Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many... (Review)
Review
Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.
Topics: Humans; Apomorphine; Levodopa; Parkinson Disease; Antiparkinson Agents; Dopamine
PubMed: 37210460
DOI: 10.1007/s00702-023-02655-0 -
CNS Drugs Nov 2016Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the... (Review)
Review
Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.
Topics: Antiparkinson Agents; Carbidopa; Catechols; Chemistry, Pharmaceutical; Drug Combinations; Humans; Levodopa; Nitriles; Parkinson Disease
PubMed: 27743318
DOI: 10.1007/s40263-016-0386-8