Dopamine D2-like receptor (Ki = 0.7 nM for D2 receptor) [1]
Dopamine D3 receptor (Ki = 1.5 nM) [1]
5-HT2B receptor (Ki = 1.2 nM) [1]

At D2, D3, and 5-HT2B receptors, cabergoline is a powerful anesthetic experimental drug. In a dose-dependent manner, cabergoline prevents the death of neuronal cells triggered by H2O2. The following investigated the neuroprotective impact of 10 μM cabergoline. Cabergoline was shown to dramatically prevent H2O2-induced neuronal death by MAP2 labeling. Cabergoline inhibits inset cell death following H2O2 exposure, as demonstrated by the detection of inset nuclear condensation [1].

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Pre-treatment with cabergoline (10 µM for 24 hours) significantly protected cultured rat cortical neurons from cell death induced by hydrogen peroxide (H2O2, 50 µM), as measured by MTT assay, MAP2 staining, and calcein-AM assay. This protective effect was dose-dependent (0.01-50 µM) and time-dependent, with maximal protection observed after 24 hours of pre-incubation. [1]
The neuroprotective effect of cabergoline against H2O2-induced cell death was abolished by the dopamine D2-like receptor antagonist spiperone (10 µM), indicating a receptor-mediated mechanism. [1]
Cabergoline (10 µM, 24h pre-treatment) significantly suppressed the activation (phosphorylation) of ERK1/2 and p38 MAPK signaling pathways induced by H2O2 (50 µM) in cortical neurons. [1]
Cabergoline (10 µM, 24h) significantly reduced the increase in extracellular glutamate levels triggered by H2O2 (50 µM for 20 min) exposure. [1]
Treatment with cabergoline (10 µM for 24 hours) increased the total protein expression levels of the glutamate transporters EAAC1 and GLT-1 in cultured cortical neurons. [1]
Cabergoline treatment (10 µM for 24 hours) did not alter the total protein expression levels of glutamate receptor subunits NR2A, NR2B, GluR1, GluR2/3, or the presynaptic protein synapsin I. A slight decrease in the cell surface expression of NR2A was observed, but no changes were found for NR2B, GluR1, or GluR2/3. [1]
Cabergoline treatment (10 µM for 3 or 24 hours) did not increase the mRNA levels of brain-derived neurotrophic factor (BDNF) in cultured cortical neurons. [1]

The female treatment sample injected with cabergoline had a 67.3% reduction in REM sleep times (F (1, 11) although = 12.892, P = 0.004), the most significant reduction in REM sleep occurred during sleep stages. The maximum amount of REM sleep occurring during the dark phase was reduced (82.3% reduction in REM sleep effect; F (1, 11) =3.667, P = 0.082). Within two injections, cabergoline decreased baseline prolactin (PRL) levels in adapters (98.5%; F (1, 6) =13.192, P=0.011) from 5.8±1.3 to 0.08 ng/mL. Following a seven-day recuperation period, PRL levels reached baseline values (5.0±0.60 ng/mL; F (1, 6) =0.715, P=0.43)[2].

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The study is primarily in vitro; however, it cites previous in vivo work: Intraperitoneal (ip) administration of cabergoline for 7 days prevented the death of dopaminergic neurons in the nigrostriatal region of male ICR mice induced by intracerebroventricular (icv) injection of 6-OHDA. [1]

Primary Cortical Neuron Culture and Drug Treatment: Cortical neurons were prepared from postnatal 1-2 day old Wistar rats. Cells were plated at a density of 5×10⁵ cells/cm² on polyethylenimine-coated plates and maintained in culture medium (DMEM/Ham's F-12 with 5% FBS, 5% HS, penicillin, and streptomycin). To inhibit glial proliferation, AraC (2 µM) was added at day 1 in vitro (DIV1). At DIV 6-7, cells were pretreated with cabergoline (typically 10 µM) for 24 hours. Following pretreatment, oxidative stress was induced by adding H₂O₂ (typically 50 µM). Inhibitors such as spiperone (10 µM, D₂ antagonist), U0126 (10 µM, ERK inhibitor), SB203580 (10 µM, p38 inhibitor), AP5 (10 µM, NMDA receptor blocker), and nifedipine (10 µM, L-type Ca²⁺ channel blocker) were applied 20 minutes before cabergoline or H₂O₂. [1]
Cell Viability Assays: Cell survival was assessed using multiple methods. For the MTT assay, after treatment, the medium was replaced with fresh medium containing MTT solution (2.5 mg/ml). Following incubation, lysis buffer (isopropyl alcohol) was added, and the absorbance was measured at 570 nm. For the calcein-AM assay, cells were washed with PBS and incubated with Calcein-AM solution. Fluorescence intensity (485/535 nm) was then measured. For immunostaining, cells were fixed with 4% paraformaldehyde, blocked, and incubated with anti-MAP2 antibody, followed by Alexa Fluor 488 secondary antibody. Nuclear condensation was assessed using Hoechst 33342 staining. [1]
Western Blotting: Cells were lysed in SDS-based lysis buffer. Equal amounts of protein were separated by SDS-PAGE and transferred to PVDF membranes. Membranes were blocked with non-fat milk and incubated with primary antibodies overnight at 4°C, followed by HRP-conjugated secondary antibodies. Immunoreactivity was visualized using chemiluminescent reagents. Protein levels of D₂ receptor, synapsin I, phosphorylated and total ERK1/2, JNK1/2, p38, NMDA receptor subunits (NR2A, NR2B), AMPA receptor subunits (GluR1, GluR2/3), and glutamate transporters (EAAC1, GLT-1) were analyzed. [1]
Cell Surface Labeling: To measure cell surface protein levels, live cortical cells were incubated with Sulfo-NHS-LC-Biotin at 4°C. After quenching with glycine, cells were lysed in RIPA buffer. Biotinylated proteins were pulled down using NeutrAvidin-conjugated agarose beads. The precipitated proteins were then eluted and analyzed by SDS-PAGE and Western blotting for surface expression of NR2A, NR2B, GluR1, and GluR2/3. [1]
Glutamate Release Measurement: Extracellular glutamate levels were measured by HPLC. Cells were washed with KRH buffer, and then incubated in KRH buffer for 20 minutes to collect baseline samples. Subsequently, cells were exposed to KRH buffer containing H₂O₂ (50 µM) for 20 minutes to measure stimulated glutamate release. The collected buffers were analyzed by HPLC. [1]
Real-Time PCR: Total RNA was extracted and reverse transcribed into cDNA using the SuperScript VILO kit. Real-time PCR was performed using TaqMan Gene Expression Assays with specific primers for BDNF and GAPDH (as an internal control) on an ABI Prism 7000 system. [1]

The study cites a previous in vivo protocol: Male ICR mice received an intracerebroventricular (icv) injection of 6-OHDA to induce neuronal damage. Cabergoline was administered intraperitoneally (ip) daily for 7 days. After this period, the survival of dopaminergic neurons in the nigrostriatal region was assessed. [1]

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The study cites a previous in vivo protocol: Male ICR mice received an intracerebroventricular (icv) injection of 6-OHDA to induce neuronal damage. Cabergoline was administered intraperitoneally (ip) daily for 7 days. After this period, the survival of dopaminergic neurons in the nigrostriatal region was assessed. [1]

Absorption, Distribution and Excretion
First-pass effect was observed, but absolute bioavailability remains unclear. In five healthy volunteers, approximately 22% and 60% of the dose were excreted in urine and feces within 20 days, respectively. Less than 4% of the dose was excreted unchanged in urine. Renal clearance = 0.008 L/min Non-renal clearance = 3.2 L/min Metabolism/Metabolites Hepatic metabolism. Cabergoline is extensively metabolized, primarily through the hydrolysis of the acylurea bond in the urea moiety. Cytochrome P-450-mediated metabolism appears to be minimal. The major metabolite identified in urine was 6-allyl-8β-carboxy-ergoline (4-6% of the dose). Three other metabolites were also detected in urine (less than 3% of the dose). Hepatic metabolism: Cabergoline is extensively metabolized, primarily through the hydrolysis of the acylurea bond in the urea moiety. Cytochrome P-450-mediated metabolism appears to be negligible. The major metabolite detected in urine was 6-allyl-8β-carboxyergoline (4-6% of the dose). Three other metabolites were also detected in urine (less than 3% of the dose).
Excretion pathway: After oral administration of radiolabeled cabergoline to five healthy volunteers, approximately 22% and 60% of the dose were excreted in urine and feces, respectively, within 20 days. Less than 4% of the dose was excreted unchanged in urine.
Half-life: Based on urine data from 12 healthy subjects, the elimination half-life was estimated to be between 63 and 69 hours.
Biological half-life
Based on urine data from 12 healthy subjects, the elimination half-life was estimated to be between 63 and 69 hours.

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Cabergoline has a long elimination half-life, ranging from 63 to 109 hours, which is longer compared to other D₂-like receptor agonists. This property leads to a long-lasting clinical effect following single-dose administration. [1]

Toxicity Summary
Ergoline alkaloids have been shown to have significant affinity for 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and α-adrenergic receptors. This can lead to a variety of effects, including vasoconstriction, seizures, and hallucinations. (A2914, A2915, A2916, L1935) The dopamine D2 receptor is a 7-transmembrane G protein-coupled receptor associated with Gi proteins. In lactating cells, activation of the dopamine D2 receptor leads to inhibition of adenylate cyclase, thereby reducing intracellular cAMP concentration and blocking the release of IP3-dependent Ca2+ from intracellular stores. The reduction in intracellular calcium levels may also be achieved by inhibiting the influx of calcium ions into voltage-gated calcium channels rather than by adenylate cyclase. Furthermore, receptor activation blocks the phosphorylation of p42/p44 MAPK and reduces the phosphorylation level of MAPK/ERK kinases. MAPK inhibition appears to be mediated by c-Raf and β-Raf-dependent MAPK/ERK kinase inhibition. Dopamine-stimulated pituitary release of growth hormone is achieved by reducing intracellular calcium ion influx into voltage-gated calcium channels rather than inhibiting adenylate cyclase. Stimulation of dopamine D2 receptors in the substantia nigra-striatal pathway improves muscle coordination in patients with movement disorders. Cabergoline is a long-acting dopamine receptor agonist with high affinity for D2 receptors. Receptor binding studies have shown that cabergoline has low affinity for dopamine D1, α1, and α2 adrenergic receptors, as well as 5-HT1 and 5-HT2 serotonin receptors.

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In the referenced cell viability assays (MTT, calcein-AM, MAP2 staining), application of cabergoline alone (10 µM or 50 µM for 36 hours) had no effect on the viability of cultured cortical neurons, indicating it was not toxic under these experimental conditions. [1]

[1]. Cabergoline, dopamine D2 receptor agonist, prevents neuronal cell death under oxidative stress via reducing excitotoxicity. PLoS One. 2014 Jun 10;9(6):e99271.

[2]. A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice. Endocrinology. 2014 Nov;155(11):4411-21.

Pharmacodynamics
Cabergoline stimulates central dopaminergic receptors, thereby producing a variety of pharmacological effects. Currently, five dopamine receptors from two dopaminergic subfamilies have been identified. The dopamine D1 receptor subfamily includes D1 and D5 subreceptors, which are associated with motor disorders. The dopamine D2 receptor subfamily includes D2, D3, and D4 subreceptors, which are associated with the improvement of motor disorder symptoms. Therefore, specific agonist activity of D2 subfamily receptors (mainly D2 and D3 receptor subtypes) is a major target for dopaminergic anti-Parkinson's disease drugs. It is believed that postsynaptic D2 receptor activation is the main reason for the anti-Parkinson's disease effect of dopamine agonists, while presynaptic D2 receptor activation has neuroprotective effects. This semi-synaptic ergoline derivative exhibits potent agonist activity against both dopamine D2 and D3 receptors. It also exhibits the following activities: agonist activity against serotonin (5-HT)_2B, 5-HT_2A, 5-HT_1D, dopamine D₄, 5-HT_1A, dopamine D₁, 5-HT_1B, and 5-HT_2C receptors (in descending order of binding affinity), and antagonist activity against α_2B, α_2A, and α_2C receptors. Parkinson's syndrome occurs when approximately 80% of the dopaminergic activity in the substantia nigra-striatal pathway of the brain is lost. Because the striatum is involved in regulating and coordinating the intensity of muscle activity (e.g., movement, balance, walking), its loss of activity can lead to dystonia (acute muscle contractions), Parkinson's syndrome (including symptoms such as bradykinesia, tremor, rigidity, and apathy), akathisia (restlessness), tardive dyskinesia (involuntary muscle movements usually associated with prolonged dopaminergic activity loss), and neuroleptic malignancy (occurring when dopamine in the substantia nigra-striatum is completely blocked). Excessive dopaminergic activity in the limbic pathway of the brain can lead to hallucinations and delusions; these side effects of dopamine agonists are common in patients with schizophrenia because this area of their brain is overactive. The hallucinogenic side effects of dopamine agonists may also be related to 5-HT2A receptor agonism. The tuberous-infundibular pathway originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits the secretion of prolactin by the lactocytes of the anterior pituitary. Increased dopaminergic activity in the tuberous-infundibular pathway inhibits prolactin secretion.

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Cabergoline is an ergot-derived dopamine D₂-like receptor agonist. It has high affinity for dopamine D2, D3, and 5-HT2B receptors. Due to its high affinity for D2 receptors, it is beneficial for dopamine replacement therapy in Parkinson's disease (PD). It is also used for treating hyperprolactinemia, ovarian hyperstimulation syndrome, Cushing's disease, and restless legs syndrome. [1]
The study suggests that the neuroprotective mechanism of cabergoline in cortical neurons under oxidative stress involves a D2 receptor-mediated pathway that suppresses ERK1/2 activation and reduces excitotoxicity by decreasing extracellular glutamate accumulation, potentially through the upregulation of glutamate transporters like EAAC1. This contrasts with its previously reported role as a direct radical scavenger in other cell types. [1]

C26H37N5O2

451.615

451.294

81409-90-7

Cabergoline-d5;1426173-20-7;Cabergoline-d6;2738376-76-4

54746

White to off-white solid powder

1.2±0.1 g/cm3

102-104°C

1.594

2.43

2

4

8

33

713

3

C(N1C[C@H](C(=O)N(CCCN(C)C)C(=O)NCC)C[C@@H]2C3C=CC=C4C=3C(=CN4)C[C@@H]12)C=C

KORNTPPJEAJQIU-KJXAQDMKSA-N

InChI=1S/C26H37N5O2/c1-5-11-30-17-19(25(32)31(26(33)27-6-2)13-8-12-29(3)4)14-21-20-9-7-10-22-24(20)18(16-28-22)15-23(21)30/h5,7,9-10,16,19,21,23,28H,1,6,8,11-15,17H2,2-4H3,(H,27,33)/t19-,21-,23-/m1/s1

(6aR,9R,10aR)-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-7-prop-2-enyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide

Cabergoline FCE-21336 CG-101

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~553.59 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)