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Deutsche Medizinische Wochenschrift... Nov 2022Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening heart disease, with onset in the last month of pregnancy or in the first months after...
Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening heart disease, with onset in the last month of pregnancy or in the first months after delivery in previously heart-healthy women. PPCM patients typically present with heart failure due to left ventricular (LV) dysfunction with an LV ejection fraction (EF) < 45 %. In the last years clinical and experimental studies contributed to a better understanding of the pathophysiology and the clinical course of PPCM. In the context of oxidative stress, the nursing hormone prolactin is cleaved into a smaller antiangiogenic and proapoptotic 16k Da form, leading to myocardial dysfunction. In an animal model this can be prevented by treatment with the dopamine agonist bromocriptine, which suppresses prolactin release. This therapeutic approach was confirmed in several clinical studies. Therefore, the current guidelines recommend a treatment consisting of a heart failure treatment according to current guidelines in combination with the dopamine agonist bromocriptine. If the diagnosis is made early and the treatment is started immediately, the prognosis is good compared to other forms of cardiomyopathies, as LV function recovers in most cases.In the acute phase the severity of heart failure differs among PPCM patients. Some patients present with mild forms, whereas some PPCM patients display severely reduced LV function and cardiogenic shock. Especially the latter cases are still challenging, as treatment with β1-adrenergic receptor agonists is associated with progression of heart failure and a worse cardiac outcome. Therefore, patients with cardiogenic shock complicating PPCM should be treated in centers experienced in mechanical circulatory support in combination with bromocriptine treatment.
Topics: Pregnancy; Humans; Animals; Female; Peripartum Period; Bromocriptine; Shock, Cardiogenic; Pregnancy Complications, Cardiovascular; Prolactin; Dopamine Agonists; Cardiomyopathies; Puerperal Disorders; Heart Failure; Ventricular Dysfunction, Left
PubMed: 36384155
DOI: 10.1055/a-1810-9318 -
Cell Reports. Medicine Oct 2023Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat...
Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.
Topics: Mice; Animals; Dopamine Agonists; Levodopa; Dopamine; Antiparkinson Agents; Parkinsonian Disorders; Dyskinesia, Drug-Induced; Oxidopamine; gamma-Aminobutyric Acid
PubMed: 37774703
DOI: 10.1016/j.xcrm.2023.101208 -
Neuroendocrinology 2022Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of... (Review)
Review
Dopamine agonists (DAs) are preferred for the treatment of prolactinomas and are usually very effective. Nonetheless, 20-30% of bromocriptine- and approximately 10% of cabergoline-treated individuals exhibit resistance to DAs. In addition, the mechanism underlying this phenomenon remains elusive. In this study, we summarize the major findings regarding the role of microRNAs (miRNAs) in the pathogenesis of DA-resistant prolactinoma (DARP). Currently available evidence suggests that miRNAs are usually dysregulated in DARP and that, although controversial, the dysregulated miRNAs target the transforming growth factor (TGF)-β, dopamine 2 receptor (D2R), or estradiol (E2)/estrogen receptor (ER) signaling pathways to mediate the therapeutic effect of DAs. These findings provide new incentives for research on innovative strategies for predicting patients' responsiveness to dopamine therapies and for developing treatment approaches. Unfortunately, recent studies tended to focus exclusively on the differential miRNA expression profiles between DARP and dopamine-sensitive prolactinoma, and no definitive consensus has been reached regarding the role of these miRNAs in the modulation mechanism. Therefore, current and future efforts should be directed toward the exploration of the mechanism underlying the dysregulation of miRNAs as well as of the target proteins that are affected by the dysregulated miRNAs. Furthermore, the modulation of the expression of dysregulated miRNAs, which target the D2R, TGF-β, or E2/ER signaling pathways, might be a promising alternative to treat patients with DARP and improve their prognosis.
Topics: Dopamine; Dopamine Agonists; Drug Resistance, Neoplasm; Humans; MicroRNAs; Pituitary Neoplasms; Prolactinoma
PubMed: 34034260
DOI: 10.1159/000517356 -
Pituitary Feb 2020Prolactinomas in men are usually large and invasive, presenting with signs and symptoms of hypogonadism and mass effects, including visual damage. Prolactin levels are... (Review)
Review
CONTEXT
Prolactinomas in men are usually large and invasive, presenting with signs and symptoms of hypogonadism and mass effects, including visual damage. Prolactin levels are high, associated with low testosterone, anemia, metabolic syndrome and if long-standing also osteoporosis.
RESULTS
Medical treatment with the dopamine agonist, cabergoline, became the preferred first-line treatment for male prolactinomas as well as for giant tumors, leading to prolactin normalization in ~ 80% of treated men, and tumor shrinkage, improved visual fields and recovery of hypogonadism in most patients. Multi-modal approach including surgery and occasionally radiotherapy together with a high-dose cabergoline is saved for resistant and invasive adenomas. Experimental treatments including temozolomide or pasireotide may improve clinical response in men harboring resistant prolactinomas.
CONCLUSIONS
Compared to other pituitary adenomas, secreting and non-secreting, where pituitary surgery is the recommended first-line treatment, men with prolactinomas will usually respond to medical treatment with no need for any additional treatment.
Topics: Cabergoline; Dopamine Agonists; Humans; Hypogonadism; Male; Pituitary Neoplasms; Prolactinoma; Somatostatin; Temozolomide
PubMed: 31802331
DOI: 10.1007/s11102-019-01009-y -
Journal of Neuroinflammation Oct 2022Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the...
BACKGROUND
Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation.
METHODS
We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence.
RESULTS
Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression.
CONCLUSIONS
Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.
Topics: Animals; Astrocytes; Corticosterone; Depression; Depressive Disorder, Major; Disease Models, Animal; Dopamine; Dopamine Agonists; Hippocampus; Inflammation; Interleukin-6; Mice; Mice, Knockout; Receptors, Dopamine D2; Stress, Psychological; beta-Arrestin 1; beta-Arrestin 2
PubMed: 36183107
DOI: 10.1186/s12974-022-02597-6 -
European Journal of Endocrinology Sep 2020There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that...
There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia. In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.
Topics: Antipsychotic Agents; Dopamine Agonists; Drug Interactions; Humans; Hyperprolactinemia; Mental Disorders; Prolactin; Prolactinoma; Receptors, Dopamine D2
PubMed: 32508315
DOI: 10.1530/EJE-20-0607 -
Practical Neurology Dec 2021
Topics: Antiparkinson Agents; Creativity; Dopamine Agonists; Humans; Levodopa; Parkinson Disease
PubMed: 34759025
DOI: 10.1136/practneurol-2021-003104 -
Pituitary Feb 2020Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite... (Review)
Review
PURPOSE
Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite dopamine agonist treatment and surgery. In some cases, metastasis occurs, defining prolactin carcinoma which is the second most frequent pituitary carcinoma.
METHODS
A literature search was performed to review the available data on the treatment of aggressive pituitary prolactinomas or carcinomas.
RESULTS
When optimal standard therapies (high dose cabergoline, surgery and radiotherapy) failed, temozolomide, an alkylating drug, is currently the best option, allowing to control tumor growth in about 50% of treated prolactinomas and improving overall survival of these patients. However, long-term complete response occurs in a limited subgroup of tumors. Alternative drugs could be discussed in a subset of aggressive prolactinomas either before temozolomide (pasireotide, peptide receptor radionuclide therapy…) or after temozolomide failure.
CONCLUSION
Despite the significant improvement obtained with the use of temozolomide, a need for alternative drugs persists since a majority of these tumors are resistant or will recur during the follow-up. Patients suffering from such a rare condition should have access to clinical trials available for other types of rare cancers, such as tyrosine kinase inhibitors or immunotherapy.
Topics: Dopamine Agonists; Humans; Pituitary Neoplasms; Prolactinoma; Temozolomide
PubMed: 31617128
DOI: 10.1007/s11102-019-01000-7 -
ACS Chemical Neuroscience Sep 2020Pramipexole was first manufactured by Pharmacia and Upjohn in July 1997 under the United States brand names of Mirapex and Mirapex ER. Pramipexole is classified as a... (Review)
Review
Pramipexole was first manufactured by Pharmacia and Upjohn in July 1997 under the United States brand names of Mirapex and Mirapex ER. Pramipexole is classified as a nonergoline aminobenzothiazole compound that selectively agonizes the dopamine D-like receptor subfamily, which includes the D, D, and D receptor subtypes. Pramipexole is a unique compound in its therapeutic potential because it has D-preferring properties. The D receptor target has implications in both motor and psychiatric symptoms of Parkinson's disease, restless leg syndrome, and bipolar and unipolar depression. Currently, pramipexole is approved to treat signs and symptoms of idiopathic Parkinson's disease and moderate to severe symptoms of primary restless leg syndrome. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, gait disorders, and a disturbance of posture due to a decrease in dopamine stores in the substantia nigra with the consequent presence of Lewy bodies. Restless leg syndrome is a neurologic sensorimotor disorder characterized by a compelling urge to move the body/limb to relieve this uncomfortable sensation. In this Review, we will discuss the synthesis, drug metabolism, pharmacology, adverse effects, history, and the importance of pramipexole to neuroscience and describe its role in therapy.
Topics: Benzothiazoles; Dopamine Agonists; Humans; Parkinson Disease; Pramipexole; Tremor
PubMed: 32786316
DOI: 10.1021/acschemneuro.0c00332 -
Medicine Dec 2022Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological... (Review)
Review
Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological developments have shown the contribution of various genetic markers, neurotransmitter dysfunction, and iron deficiency to the disease, as well as other unidentified contributing mechanisms, particularly chronic renal dysfunction. RLS enhancement syndrome is frequently observed in patients with RLS who have received long-term dopamine agonist therapy, manifesting as a worsening of RLS symptoms, usually associated with an increase in the dose of dopamine agonist. Some patients with RLS can adequately control their symptoms with non-pharmacological measures such as massage and warm baths. First-line treatment options include iron supplementation for those with evidence of reduced iron stores, or gabapentin or pregabalin, as well as dopamine agonists, such as pramipexole. Second-line therapies include opioids such as tramadol. RLS seriously affects the quality of life of patients, and because its pathogenesis is unclear, more biological evidence and treatment methods need to be explored.
Topics: Humans; Dopamine Agonists; Restless Legs Syndrome; Quality of Life; Gabapentin; Iron
PubMed: 36550837
DOI: 10.1097/MD.0000000000032324