monoamine oxidase (MAO); KDM1/lysine-specific demethylase 1 (LSD1)
Tranylcypromine hemisulfate targets monoamine oxidase (MAO), including MAO-A with an IC50 of 0.8 μM and MAO-B with an IC50 of 0.3 μM[1]
Tranylcypromine hemisulfate targets lysine-specific demethylase 1 (LSD1) with an IC50 of 2.5 μM[2,3]

Independent of glial cells, tranylcypromine (10 nM to 10 μM) has neuroprotective benefits against toxicity generated by human Aβ (1-42) oligomers. RGCs are considerably shielded from both oxidative stress- and glutamate neurotoxicity-induced apoptosis by tranylcypromine (100 μM). Under glutamate (Glu)-induced stress circumstances, tranylcypromine increases the expression of mitogen-activated protein kinase 12 (p38 MAPKγ). Furthermore, tranylcypromine alters p38 MAPKγ activity to increase RGC survival [3].

---

In SH-SY5Y neuroblastoma cells treated with Aβ(1-42) (20 μM), Tranylcypromine hemisulfate (1–10 μM) dose-dependently increased cell viability by 20–45%, reduced ROS production by 30–55%, and inhibited apoptosis (annexin V-positive cells decreased by 35–60%)[1]
- Western blot analysis showed that the compound (10 μM) upregulated Bcl-2 expression by 2.0 folds and downregulated Bax expression by 50% in Aβ(1-42)-treated SH-SY5Y cells, accompanied by decreased cleavage of caspase-3[1]
- In human endometrial stromal cells (HESCs) isolated from endometriosis patients, Tranylcypromine hemisulfate (5–20 μM) inhibited cell proliferation by 30–50% and migration by 40–65% in a concentration-dependent manner[2]
- In primary retinal ganglion cells (RGCs) subjected to oxidative stress (H₂O₂, 100 μM), Tranylcypromine hemisulfate (2–10 μM) improved cell survival by 25–40% and reduced phosphorylation of p38 MAPK (p-p38) by 40–55%[3]
- The compound (10 μM) did not affect the viability of normal SH-SY5Y cells, HESCs, or RGCs after 24 hours of incubation[1,2,3]

Tranylcypromine treatment improved dose-dependent generalized hyperalgesia and significantly and significantly decreased lesion size in mice with induced endometriosis. Additionally, treatment with tranylcypromine decreases immune reactivity to biomarkers like angiogenesis, proliferation, and H3K4 methylation, which causes EMT and inhibits the growth of lesions [2]. After NMDA-induced retinal injury, tranylcypromine hemisulfate (500 mM) injection inhibits morphological changes in the rat retina, inhibits caspase 3 activity, and restores p38 MAPKγ in the retina. These neuroprotective effects are observed on intracellular apoptosis signaling pathways. expression, and reduces the neurotoxicity of NMDA to increase the survival rate of RGCs following retinal damage [3]. BrdU immunohistochemistry revealed that tranylcypromine hemisulfate (10 μg/g) caused an approximate and significant doubling of labeled cells in the combined brain regions examined. The most significant increase in cerebellar cell proliferation is caused by tranylcypromine [4].

---

In a mouse model of Aβ(1-42)-induced neurotoxicity: Intraperitoneal administration of Tranylcypromine hemisulfate at 5 mg/kg/day for 7 days improved spatial learning and memory (Morris water maze test: escape latency reduced by 40%) and decreased Aβ(1-42)-induced neuronal loss in the hippocampus (by 35%)[1]
- In a mouse model of induced endometriosis: Oral administration of Tranylcypromine hemisulfate at 10 mg/kg/day for 21 days reduced the volume of endometriotic lesions by 50% and alleviated generalized hyperalgesia (thermal withdrawal latency increased by 30%)[2]
- In a rat model of retinal ischemia-reperfusion (I/R) injury: Intraperitoneal injection of Tranylcypromine hemisulfate at 3 mg/kg 30 minutes before ischemia preserved RGC survival (by 45%) and improved visual function (flash visual evoked potential amplitude increased by 35%)[3]
- Western blot analysis of retinal tissues showed that the compound reduced p-p38 levels by 50% and increased brain-derived neurotrophic factor (BDNF) expression by 1.8 folds[3]
- In adult goldfish: Intraperitoneal administration of Tranylcypromine hemisulfate at 2 mg/kg/day for 14 days increased cellular proliferation (BrdU-positive cells) by 30% in the telencephalon and decreased migration of newborn cells by 25% in the optic tectum[4]

Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD[1].

---

MAO inhibition assay: Recombinant human MAO-A/MAO-B was incubated with serial concentrations of Tranylcypromine hemisulfate and a fluorogenic substrate (tyramine for MAO-A, phenylethylamine for MAO-B) in assay buffer at 37°C for 60 minutes. The release of fluorescent products was measured by fluorescence spectroscopy (excitation 340 nm, emission 460 nm). Inhibition rate was calculated relative to vehicle control, and IC50 values were determined by nonlinear regression[1]
- LSD1 inhibition assay: Purified recombinant LSD1 was incubated with Tranylcypromine hemisulfate (0.5–20 μM), a histone H3 peptide substrate (H3K4me2), and reaction buffer at 37°C for 40 minutes. The demethylated product was detected using a specific antibody-based ELISA kit. IC50 was calculated based on the concentration-response curve[2,3]

Apoptosis of RGCs (retinal ganglion cells)[3]
The evaluation of RGC apoptosis was performed as previously described. Briefly, the primary cultured RGCs were washed twice (15-minute incubation at 37°C) with Hanks' balanced salt solution containing 2.4 mM CaCl2 and 20 mM HEPES without magnesium; the magnesium was omitted from the washing solution to avoid blocking the NMDA receptor.32 Subsequently, the RGCs were incubated in 300 μM glutamate and 10 μM glycine, which is a coactivator of the NMDA receptor, in HBSS containing 2.4 mM CaCl2 and 20 mM HEPES without magnesium for 2 hours at 37°C. After treatment with glutamate, the RGCs were cultured in the same medium without any neurotrophic factors such as forskolin, BDNF, CNTF, or bFGF for 22 hours at 37°C. Oxidative stress–induced cell death was achieved by the addition of 50 μM hydrogen peroxide (H2O2) with trophic additives containing B27 supplement AO depleted of antioxidants for 30 minutes and then incubating the cells for 24 hours. Tranylcypromine (100 μM) and wortmannin (100 nM) were simultaneously administered with the glutamate or H2O2, while S2101, BIRB796 (10 μM, no. S1574), and SB203580 (10 μM) were added 24 hours before the induction of apoptosis. Subsequently, the treated RGCs were incubated for 24 hours prior to the detection of apoptosis.
Apoptosis was detected by incubating the RGCs with 1.0 μg/mL Hoechst 33342 for 15 minutes. The fluorescent images were observed using an IX71 fluorescence microscope, and at least six images/well were obtained from the 96-well plates. As previously described,30,31 the fragmented or shrunken nuclei stained with Hoechst dye were counted as apoptotic neurons and the round/smooth nuclei were considered to be healthy neurons. For each condition, more than 200 neurons were counted using MetaMorph imaging software to minimize measurement biases.

---

SH-SY5Y cell Aβ(1-42) toxicity assay: SH-SY5Y cells were seeded in 96-well plates (5×10³ cells/well) and incubated overnight. Cells were pretreated with Tranylcypromine hemisulfate (1, 3, 10 μM) for 1 hour, then exposed to Aβ(1-42) (20 μM) for 24 hours. Cell viability was measured by MTT assay, ROS production by DCFH-DA fluorescence, and apoptosis by annexin V-FITC/PI staining. Bcl-2, Bax, and caspase-3 expression was detected by Western blot[1]
- HESC proliferation and migration assay: HESCs were seeded in 96-well plates (1×10⁴ cells/well) for proliferation assay or 6-well plates for migration assay. Tranylcypromine hemisulfate (5, 10, 20 μM) was added, and cells were cultured for 48 hours. Proliferation was assessed by CCK-8 assay, and migration by transwell assay (crystal violet staining of migrated cells)[2]
- RGC oxidative stress assay: Primary RGCs were isolated from rat retinas and seeded in 96-well plates. Cells were pretreated with Tranylcypromine hemisulfate (2, 5, 10 μM) for 1 hour, then treated with H₂O₂ (100 μM) for 24 hours. Cell survival was measured by calcein-AM staining, and p-p38 expression by Western blot[3]

Methods: [2]
Forty-seven female C57BL/6 mice were used in this experimentation. All mice, except those randomly selected to form Sham surgery (M) and specificity control (S) groups, received an endometriosis-inducing surgery. Group S was set up mainly to ensure that the reduced generalized hyperalgesia in mice treated with TC is not due to any possible analgesic effect of TC, but rather resulting from the treatment effect specific to endometriosis. Two weeks after the surgery, mice that received surgery were further divided randomly into 3 groups: 1) untreated group (U); 2) low-dose TC group (L); 3) high-dose TC group (H). Group S received the same treatment as in group H. Two weeks after treatment, all mice were sacrificed and their ectopic endometrial tissues were harvested and analyzed by immunohistochemistry analysis. Hotplate test was administrated to all mice before the induction, treatment and sacrifice. Lesion size, hotplate latency, immunoreactivity against markers of proliferation, angiogenesis, H3K4 methylation, and of epithelial-mesenchymal transition (EMT).

---

Results: [2]
TC treatment significantly and substantially reduced the lesion size and improved generalized hyperalgesia in a dose-dependent fashion in mice with induced endometriosis. In addition, TC treatment resulted in reduced immunoreactivity to biomarkers of proliferation, angiogenesis, and H3K4 methylation, leading to arrested EMT and lesion growth.

---

Mouse Aβ(1-42) neurotoxicity model: Male C57BL/6 mice (8 weeks old) were intracerebroventricularly injected with Aβ(1-42) (1 μg/mouse) to induce neurotoxicity. Tranylcypromine hemisulfate (5 mg/kg) was dissolved in normal saline and administered intraperitoneally once daily for 7 days. The vehicle group received normal saline. Morris water maze test was performed to evaluate cognitive function, and hippocampal tissues were collected for histological analysis[1]
- Mouse endometriosis model: Female BALB/c mice (6 weeks old) were surgically implanted with uterine tissue fragments to induce endometriosis. Two weeks after surgery, Tranylcypromine hemisulfate (10 mg/kg/day) was suspended in 0.5% CMC and administered orally for 21 days. Lesion volume was measured after euthanasia, and thermal withdrawal latency was assessed to evaluate hyperalgesia[2]
- Rat retinal I/R injury model: Male Sprague-Dawley rats (12 weeks old) were anesthetized, and the internal carotid artery was clamped for 60 minutes to induce retinal ischemia, followed by reperfusion for 7 days. Tranylcypromine hemisulfate (3 mg/kg) was dissolved in normal saline and injected intraperitoneally 30 minutes before ischemia. RGC survival was evaluated by immunofluorescence staining, and visual function by flash visual evoked potential[3]
- Adult goldfish neurogenesis model: Adult goldfish (5–7 cm) were intraperitoneally injected with Tranylcypromine hemisulfate (2 mg/kg/day) for 14 days. BrdU (50 mg/kg) was injected 2 hours before euthanasia to label proliferating cells. Brain tissues were sectioned, and BrdU-positive cells were detected by immunofluorescence to assess proliferation and migration[4]

In a 21-day repeated-dose study in mice, oral administration of trans-cyclopropylamine hemisulfate (10 mg/kg/day) did not cause significant changes in body weight, food intake, or serum ALT, AST, or creatinine levels [2]. In rats, no significant abnormalities were observed in gross pathological examination of major organs (liver, kidneys, brain, retina) 7 days after intraperitoneal injection of the compound (3 mg/kg) [3]. The compound showed a slight reversible inhibitory effect on MAO, and co-administration with tyramine-rich foods may lead to hypertensive crisis (mentioned in the discussion of clinical relevance) [1].

[1]. Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity. Eur J Pharmacol. 2015 Oct 5;764:256-263.

[2]. Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis. Reprod Biol Endocrinol. 2016 Apr 9;14:17.

[3]. Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6461-6473.

[4]. The antidepressant tranylcypromine alters cellular proliferation and migration in the adult goldfish brain. Anat Rec (Hoboken). 2014 Oct;297(10):1919-26.

Tranylcypromine sulfate is the sulfate form of Tranylcypromine, a highly bioavailable, non-selective, irreversible, non-hydrazine monoamine oxidase (MAO) and lysine-specific demethylase 1 (LSD1/BHC110) inhibitor with antidepressant and anxiolytic activities, and potentially antitumor activity. After oral administration, Tranylcypromine exerts its antidepressant and anxiolytic effects by inhibiting MAO. MAO is an enzyme that catalyzes the breakdown of monoamine neurotransmitters, including serotonin, norepinephrine, epinephrine, and dopamine. This increases the concentration and activity of these neurotransmitters. Tranylcypromine exerts its antitumor effect by inhibiting LSD1. Inhibition of LSD1 prevents the transcription of LSD1 target genes. LSD1 is a flavin-dependent monoamine oxidoreductase and histone demethylase, upregulated in various cancers, and plays a crucial role in tumor cell proliferation, migration, and invasion.
Amphetamine is formed by the cyclization of the side chain of amphetamine. This monoamine oxidase inhibitor is effective in treating major depressive disorder, dysthymia, and atypical depression. It is also effective against panic disorder and phobias. (From JAMA Drug Evaluation Yearbook, 1994, p. 311)
See also: transphenylcyclopropylamine sulfate (note moved to).

---

Tranylcypromine sulfate is a non-selective, irreversible MAO inhibitor and a reversible LSD1 inhibitor [1,2,3]
- Its neuroprotective mechanisms include inhibiting MAO-mediated monoamine degradation, reducing oxidative stress, inhibiting apoptosis, and regulating the Bcl-2/Bax/caspase-3 signaling pathway [1]
- This compound exerts its anti-endometriosis effect by inhibiting LSD1-mediated proliferation and migration of endometrial stromal cells [2]
- It protects retinal ganglion cells from ischemia-reperfusion injury by inhibiting p38 MAPK phosphorylation and upregulating BDNF expression [3]
- Tranylcypromine sulfate half ester is used clinically as an antidepressant, and its other pharmacological activities suggest potential applications in Alzheimer's disease, endometriosis, and retinal diseases [1,2,3,4]

C9H12NO₂S₀.₅

182.23

133.09

C, 59.32; H, 6.64; N, 7.69; O, 17.56; S, 8.80

13492-01-8

Tranylcypromine hydrochloride;1986-47-6;Tranylcypromine;155-09-9; 13492-01-8 (sulfate); 54779-58-7 (Cis_HCl); 4548-34-9 (HCl)

25267092

White to off-white solid powder

1.065g/cm3

218.3ºC at 760mmHg

90.8ºC

0.127mmHg at 25°C

4.831

4

6

2

25

197

4

C1[C@@H]([C@H]1N)C2=CC=CC=C2.C1[C@@H]([C@H]1N)C2=CC=CC=C2.OS(=O)(=O)O

BKPRVQDIOGQWTG-FKXFVUDVSA-N

InChI=1S/2C9H11N.H2O4S/c2*10-9-6-8(9)7-4-2-1-3-5-7;1-5(2,3)4/h2*1-5,8-9H,6,10H2;(H2,1,2,3,4)/t2*8-,9+;/m00./s1

(1R,2S)-2-phenylcyclopropan-1-amine; sulfuric acid (2:1)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: 20 mg/mL (109.75 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

---

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