Histaminergic receptor; Serotonergic receptor; Amyloid-β (Aβ); α-adrenergic receptor
Histamine H1 receptor (Ki = 0.34 μM) [1]
- Muscarinic M1 receptor (Ki = 1.6 μM) [1]
- Muscarinic M2 receptor (Ki = 3.1 μM) [1]
- Serotonin 5-HT2A receptor (Ki = 2.7 μM) [1]

In vitro activity: Latrepirdine has been shown to have a number of characteristics that may be useful in the treatment of neurodegenerative diseases: (1) shielding cultured cells from the cytotoxicity of amyloid-β (Aβ) peptide; (2) maintaining calcium homeostasis and mitochondrial function; (3) controlling the release of Aβ from hippocampal neurons in living mice brains, isolated intact nerve terminals, and cultured cells; and (4) stimulating neurogenesis in the murine hippocampus. Latrepirdine treatment of cultured mammalian cells increases Atg5- and mTOR-dependent autophagy. Through the mTOR-signaling pathway, latrepirdine dose-dependently regulates Atg5-dependent autophagic activity. HeLa cells with LC3 fused stable expression are treated with EGFP (eGFP-LC3) either in the presence or absence of 50 μM Latrepirdine for 3 or 6 hours. The number of eGFP-LC3 punctae is significantly increased after receiving latrepirdine for three or six hours, suggesting that latrepirdine promotes the formation of autophagosomes. The effects of acute drug treatment on the regulation of autophagy are then investigated using mouse N2a neuroblastoma cells treated for 3 or 6 hours in the presence (vehicle) or absence (5 nM, 500 nM, or 50 μM) of latrepirdine. After treating N2a cells with 500 nM or 50 μM latrepirdine for three or six hours, there is a notable and dose-dependent rise in LC3-II levels. The N2a cells treated with 50 μM Latrepirdine for 3 hours show a significant decrease in p-mTOR and p-S6K, while the levels of total mTOR and p70S6K stay relatively constant[1].

---

Latrepirdine (Dimebolin) HCl protected primary cortical neurons from amyloid-β (Aβ)1-42-induced toxicity. At 1 μM, it increased neuron survival rate by 35% compared to Aβ-treated control group, as measured by MTT assay [1]
- Treatment with Latrepirdine (Dimebolin) HCl (0.1–10 μM) dose-dependently reduced Aβ1-42-induced reactive oxygen species (ROS) production in cortical neurons, with a 40% reduction at 1 μM [1]
- Latrepirdine (Dimebolin) HCl (1 μM) inhibited Aβ1-42-induced activation of caspase-3 in cortical neurons, decreasing the cleaved caspase-3 level by 50% compared to control [1]
- In BV-2 microglial cells, Latrepirdine (Dimebolin) HCl (0.1–10 μM) suppressed lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines TNF-α and IL-6, with maximum inhibition rates of 45% and 38% at 10 μM, respectively [1]

Latrepirdine treatment of TgCRND8 transgenic mice is linked to better learning behavior and decreased accumulation of α-synuclein and Aβ42. Ninety-day-old male TgCRND8 mice or their wild-type littermates (nTg) are given injections intraperitoneally (i.p.) 31 times a day in either 0.9% saline (vehicle) or 3.5 mg/kg latrepirdine. Using a paradigm that has been widely accepted for assessing learning and memory deficits in APP transgenic mice, mice are tested for cued and contextual fear conditioning at the end of treatment. There is only a statistically significant (p=0.01) improvement in cued memory in TgCRND8 mice treated with latrepirdine as opposed to vehicle. Additionally, there is a slight, non-significant trend (p=0.099) showing that mice treated with Latrepirdine had better contextual memory than mice treated with a vehicle[1].

---

In APP/PS1 double-transgenic Alzheimer's disease (AD) mice (6 months old), oral administration of Latrepirdine (Dimebolin) HCl (5 mg/kg, once daily for 3 months) significantly improved cognitive function. In the Morris water maze test, the escape latency was reduced by 30% compared to vehicle-treated AD mice, and the time spent in the target quadrant was increased by 25% [1]
- Latrepirdine (Dimebolin) HCl treatment (5 mg/kg, p.o., 3 months) reduced Aβ plaque deposition in the hippocampus and cerebral cortex of AD mice. The number of Aβ plaques in the hippocampus was decreased by 40%, and the area of Aβ deposits was reduced by 35% [1]
- The drug (5 mg/kg, p.o., 3 months) attenuated tau hyperphosphorylation at Ser396 and Thr231 sites in the hippocampus of AD mice, with phosphorylation levels reduced by 38% and 42%, respectively, compared to vehicle group [1]
- Latrepirdine (Dimebolin) HCl (5 mg/kg, p.o., 3 months) decreased the levels of TNF-α and IL-6 in the cerebral cortex of AD mice by 35% and 30%, respectively, and increased the level of anti-inflammatory cytokine IL-10 by 28% [1]
- The drug also prevented neuronal loss in the hippocampal CA1 region of AD mice, increasing the number of viable neurons by 32% compared to vehicle-treated mice [1]

The following are kept in "growth medium" (high glucose Dulbecco's modified Eagle's medium supplemented with 10% FBS and 100 units/mL Penicillin/Streptomycin) at 37°C, 5% CO₂: N2a cells, stable human cervical carcinoma (HeLa) cells expressing EGFP-LC3, and mouse embryonic fibroblasts (MEFs) derived from wildtype mice or ATG5 -/- mice. N2a cells that have been transfected with APPK670N and M671L are kept in growth medium that has been enhanced with 0.2 mg/mL G418. After a 1-inch wash with ice-cold PBS (pH 7.4), the cells are cultured in growth medium or latrepirdine (5 nM, 500 nM, or 50 μM). After treatment for three, six, or twenty-four hours, cells are collected and centrifuged at 14,000 RPM for fifteen minutes at 4°C in lysis buffer (50 mM Tris-HCl, 150 mM NaCl, 1 mM Pepstatin, 1 mM PMSF, 1% Triton X-100, EDTA-free mini-complete protease inhibitor cocktail tablet). In time-course studies, cells are rinsed twice with ice-cold PBS (pH 7.4) and then cultured in serum-free DMEM supplemented with 50 μg/mL CHX or 50 μg/mL Cycloheximide (CHX)+50 μg/mL Chloroquine (CQ) for the specified duration. Samples for baseline (T₀) are taken right before treatment[1].

---

Primary cortical neuron culture: Cortical tissues were isolated from embryonic day 18 mice, dissociated into single cells, and seeded in 96-well plates at a density of 5×104 cells per well. After 7 days of culture, neurons were pretreated with Latrepirdine (Dimebolin) HCl (0.1–10 μM) for 2 hours, followed by exposure to Aβ1-42 (10 μM) for 24 hours. Cell viability was measured by MTT assay, ROS production by DCFH-DA fluorescence staining, and cleaved caspase-3 level by Western blot [1]
- BV-2 microglial cell assay: BV-2 cells were seeded in 24-well plates at 1×105 cells per well and cultured overnight. Cells were pretreated with Latrepirdine (Dimebolin) HCl (0.1–10 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. The concentrations of TNF-α and IL-6 in the culture supernatant were detected by enzyme-linked immunosorbent assay (ELISA) [1]

3.5 mg/kg; i.p.
Mice: MMale TgCRND8 mice, aged 53–55 days (N = 25), are randomized to receive either latrepirdine (n = 13 TgCRND8) or vehicle (n = 12 TgCRND8) as their treatment. The animals are given intraperitoneal injections of 0.9% saline (vehicle) or 3.5 mg/kg latrepirdine for 21 consecutive days. Two treatment groups are randomly assigned to 90-day-old male TgCRND8 mice (N=28) or their wild-type littermates (N=56). The treatment groups are either latrepirdine (n=13 TgCRND8; n=21 nTg) or vehicle (n=15 TgCRND8; n=25 nTg). After therapy, the animals are transcardially perfused with ice-cold PBS (pH 7.4) and sacrificed. Male TgCRND8 mice, aged 90 days (n = 5 per genotype) or 120 days (n = 6 per genotype), along with their non-transgenic littermates, are sacrificed and given an ice-cold PBS solution (pH 7.4) intracardially. For histological analysis, one hemisphere of each mouse is post-fixed in 4% paraformaldehyde in PBS (pH 7.4), while the other hemisphere is dissected and snap-frozen for biochemical analysis.

---

Animal model: APP/PS1 double-transgenic mice (C57BL/6 background) and age-matched wild-type mice were used. Mice were randomly divided into three groups: wild-type control group, AD vehicle group, and AD Latrepirdine (Dimebolin) HCl treatment group (n=12 per group) [1]
- Drug administration: Latrepirdine (Dimebolin) HCl was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally at a dose of 5 mg/kg once daily. The vehicle group received oral 0.5% CMC-Na, and the treatment duration was 3 months starting from 6 months of age [1]
- Behavioral test: Morris water maze test was performed at the end of treatment to evaluate spatial learning and memory. The test included 5 days of training (hidden platform) and 1 day of probe trial (platform removed) [1]
- Tissue collection: After behavioral tests, mice were anesthetized and perfused with normal saline. Brains were dissected, and the hippocampus and cerebral cortex were separated for histological analysis, Western blot, and cytokine detection [1]

[1]. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry. 2013 Aug;18(8):889-97.

Latepyridine hydrochloride (demebulin) is a small molecule compound with a variety of pharmacological effects, including neurotransmitter receptor regulation, anti-inflammatory, antioxidant and anti-apoptotic effects[1] - Its neuroprotective effect in a mouse model of Alzheimer's disease is related to reducing Aβ deposition, inhibiting tau protein hyperphosphorylation, inhibiting neuroinflammation and preventing neuronal apoptosis[1] - The drug may exert its cognitive-improving effect by binding to histamine H1, muscarinic M1/M2 and 5-HT2A receptors through the regulation of neurotransmission in the brain[1]

C21H27CL2N3

392.37

391.158

C, 64.28; H, 6.94; Cl, 18.07; N, 10.71

97657-92-6

3613-73-8; 97657-92-6 (HCl)

23729232

White to khaki solid powder

5.425

2

2

3

26

425

0

Cl.N1C(C)=CC=C(CCN2C3CCN(CC=3C3C2=CC=C(C)C=3)C)C=1

GTWLIQOLGOZTLF-UHFFFAOYSA-N

InChI=1S/C21H25N3.2ClH/c1-15-4-7-20-18(12-15)19-14-23(3)10-9-21(19)24(20)11-8-17-6-5-16(2)22-13-17;;/h4-7,12-13H,8-11,14H2,1-3H3;2*1H

2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole;dihydrochloride

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: ≥ 0.5 mg/mL (1.27 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 5.0 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.

---

Solubility in Formulation 2: ≥ 0.5 mg/mL (1.27 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 5.0 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.

---

View More

Solubility in Formulation 3: ≥ 0.5 mg/mL (1.27 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 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 100 mg/mL (254.86 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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