Amitriptyline

Amitriptyline is an orally active tricyclic antidepressant (TCA). Amitriptyline mainly exerts its antidepressant effect by blocking SERT (K_i = 3.45 nM) and NET (K_i = 13.3 nM), thereby increasing the concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in the synaptic cleft. Amitriptyline is also an agonist at α2A and TrkA/TrkB receptors, thereby exerting analgesic and neurotrophic activities (inhibiting cell apoptosis). Amitriptyline can reduce inflammation, angiogenesis and fibrosis. Amitriptyline binds to DAT (with K_i = 2.58 μM). Amitriptyline has high affinity for a series of receptors and can antagonize muscarinic cholinergic receptors (M1/M2/M3/M4/M5 receptors) (K_i = 11-24 nM), H1 receptors (K_i = 0.5-1.1 nM), adrenergic α1 receptors (K_i = 4.4 nM), etc., resulting in a series of side effects. Amitriptyline can block sodium channels and hERG potassium channel (IC₅₀ = 4.78 μM) and it has cardiotoxicity^{[1][2][3][4][5]}. In Vitro:Amitriptyline (0.5-10 μM, 3.5-16.5 h) effectively resists cell apotosis (EC₅₀ = 50 nM) in T17 cells and shows no protective effect on the SN56 cells, and in primary rat hippocampal neurons stimulated by glutamate and subjected to oxygen-glucose deprivation (OGD), the neuronal apoptosis is significantly reduced^[3].
Amitriptyline (0.5 μM, 30 min) induces TrkA and TrkB receptor phosphorylation and activation in hippocampal neurons^[3].
Amitriptyline (0.5 μM, 5 days) induces neurite outgrowth in PC12 cells^[3].
In Vivo:Amitriptyline (15 mg/kg, i.p., once daily for 5 days) prevents Kainic acid (HY-N2309)-induced neuronal apoptosis in mice brain by activating TrkA and TrkB receptors^[3].
Amitriptyline (15 mg/kg, i.p., single dose) produces antinociception in a mouse model by activating α2A-adrenoceptor receptors in the central nervous system^[4].
Amitriptyline (5 mg/kg, p.o., once daily for 7 days) is able to down-regulate angiogenesis and foreign body reaction (FBR) in 14-day-old implants^[5].