Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease (original) (raw)
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Reviews in The Neurosciences, 1997
Accumulating evidence suggests that L-dihydroxyphenylalanine (L-DOPA) has neurotransmitter-like and/or neuromodulatory properties in the CNS. Such evidence is based on a wide range of findings including the existence of specific L-DOPAergic neurons in several regions of the CNS, neurotransmitter-like characteristics and specific pharmacological effects. This review attempts to outline the main evidence for this conception and to relate such findings to L-DOPA treatment effects in Parkinson's disease. In this context L-DOPA in itself has been shown to potentiate D 2 receptor-mediated effects, inhibit acetylcholine release and increase the release of L-glutamate, neuropharmacological effects which can be linked to treatment side-effects in advanced Parkinson's disease. It is suggested that supersensitive L-DOPAmediated effects contribute to the pathogenesis underlying L-DOPA-induced motor complications in advanced Parkinson's disease. However, since specific L-DOPA receptors have yet to be identified, the assessment of the relative importance of L-DOPA-mediated effects in this clinical context must be regarded as incomplete.
Neuroscience Research Communications, 1996
Patients suffering from Parkinson's disease (PD) display severe and progressive deficits in motor behavior, predominantly as a consequence of the degeneration of dopaminergic neurons, located in the mesencephalon and projecting to striatal regions. The cause of PD is still an enigma. In general, pharmacotherapy comprises symptomatic treatment with dopaminergic compounds, which induce a dramatic initial improvement, although serious problems gradually develop after longterm treatment. This paper describes some recent investigations in pathogenetic, diagnostic and pharmacotherapeutic mechanisms related to dopaminergic systems and PD, as they have been performed in our group.
Dopamine Systems in Parkinson's Disease and L-DOPA-induced Dyskinesia What Goes Wrong?
s disease (PD) is a neurological disorder characterized by a progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta (SNc). 1 Dopaminergic neurons of the SNc send their axons along the nigrostriatal pathway to the striatum, where dopamine (DA) acts to modulate post-synaptic signaling. The striatum comprises a heterogeneous population of neurons that receives input from a number of regions, including motor and sensory cortices, and under the influence of DA utilizes this information to guide motor
Mechanism of action of dopaminergic agents in Parkinson's disease
Neurology, 1998
As the substantia nigra degenerates in Parkinson's disease (PD), the nigrostriatal pathway is disrupted, reducing striatal dopamine and producing PD symptoms. Although dopamine does not readily cross the bloodbrain barrier, its precursor, levodopa, does. Levodopa is absorbed in the small bowel and is rapidly catabolized by aromatic-L-amino-acid decarboxylase (AADC) and catechol-0-methyltransferase (COMT). Because gastric AADC and COMT degrade levodopa, the drug is given with inhibitors of AADC (carbidopa or benserazide), and inhibitors of COMT will also enter clinical use. Although the exact site of decarboxylation of exogenous levodopa to dopamine in the brain is unknown, most striatal AADC is located in nigrostriatal dopaminergic nerve terminals. Newly synthesized dopamine is stored in the terminals and then released, stimulating postsynaptic dopamine receptors and mediating the antiparkinsonian action of levodopa. Dopamine agonists act directly on postsynaptic dopamine receptors, thus obviating the need for metabolic conversion, storage, and release. How the actions of dopaminergic drugs produce side effects and how these side effects should be managed are discussed.
Neuropathology, 2004
Parkinson's disease. The 6-hydroxydopamine-lesioned rat exhibiting behavioral sensitization to L-DOPA is one useful animal model for examining L-DOPA-induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6hydroxydopamine-lesioned rats treated with L-DOPA were examined. Intermittent L-DOPA treatment induced hypertrophy of the lesioned-side of medial globus pallidus and substantia nigra reticulata of 6-hydroxydopaminelesioned rats with behavioral sensitization to L-DOPA. Additionally, coadministration of a 5-HT 1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin with L-DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L-DOPA in 6-hydroxydopamine-lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L-DOPA-induced dyskinesia in patients with Parkinson's disease.
L-Dopa induced dyskinesias in Parkinsonian mice: disease severity or L-Dopa history
Brain research, 2015
In Parkinson's disease, the efficacy of L-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson's disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of L-Dopa treatment determines development of L-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with L-Dopa (10mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to L-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting L-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlie...
Molecular Effects of L-dopa Therapy in Parkinson’s Disease
Current Genomics, 2014
Parkinson's disease (PD) is one of the most common neurological diseases in elderly people. The mean age of onset is 55 years of age, and the risk for developing PD increases 5-fold by the age of 70. In PD, there is impairment in both motor and nonmotor (NMS) functions. The strategy of PD motor dysfunction treatment is simple and generally based on the enhancement of dopaminergic transmission by means of the L-dihydroxyphenylalanine (L-dopa) and dopamine (DA) agonists. L-dopa was discovered in the early-60's of the last century by Hornykiewicz and used for the treatment of patients with PD. L-dopa treatment in PD is related to decreased levels of the neurotransmitter (DA) in striatum and absence of DA transporters on the nerve terminals in the brain. L-dopa may also indirectly stimulate the receptors of the D1 and D2 families. Administration of L-dopa to PD patients, especially long-time therapy, may cause side effects in the form of increased toxicity and inflammatory response, as well as disturbances in biothiols metabolism. Therefore, in PD patients treated with L-dopa, monitoring of oxidative stress markers (8-oxo-2'-deoxyguanosine, apoptotic proteins) and inflammatory factors (high-sensitivity C-reactive protein, soluble intracellular adhesion molecule), as well as biothiol compounds (homocysteine, cysteine, glutathione) is recommended. Administration of vitamins B6, B12, and folates along with an effective therapy with antioxidants and/or anti-inflammatory drugs at an early stage of PD might contribute to improvement in the quality of the life of patients with PD and to slowing down or stopping the progression of the disease.
Current and Potential Treatments of Parkinson's Disease
Parkinson's disease (PD), initially reported by James Parkinson in 1817, is a multisystem progressive neurodegenerative and a chronic disorder of the nervous system affecting the nerve cells. Although the aetiology of PD is still unknown, it primarily results from impaired dopaminergic neurons in the substantia nigra of the ventral mid-brain, located in the basal ganglia that controls balance and movement of the body. These nerve cells in the substantial nigra are the one responsible for production of Dopamine. The neurotransmitter dopamine is a chemical that transmits signals between neurons (or synapses) of the brain, which further possesses an effect on the rest of the body via the central nervous system. Dopamine plays a variety of roles in the brain such as voluntary movement, cognition, behaviour, sleep, mood, and working memory. Reduced dopamine activity in the substantia nigra pars compact (SNpc) with a successive loss of dopaminergic projections in the ventral striatum to both the putamen and caudate, causes an imbalance with other neurotransmitters leading a disarray of both motor and non-motor symptoms that become worse over time (Przedborski, 2003).