Amitriptyline protects against TNF-alpha-induced atrophy and reduction in synaptic markers via a Trk-dependent mechanism.

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O'Neill E, Kwok B, Day JS, Connor TJ, Harkin A

Amitriptyline protects against TNF-alpha-induced atrophy and reduction in synaptic markers via a Trk-dependent mechanism.

Pharmacol Res Perspect. 2016 Mar 8;4(2):e00195. doi: 10.1002/prp2.195. eCollection 2016 Apr.

PubMed ID

27069625 [ View in PubMed

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Abstract

Neuritic degeneration and synaptic loss are features of both neuroinflammation and neurodegenerative disease. The tricyclic antidepressant amitriptyline has neurotrophic and anti-inflammatory properties and acts as a novel agonist of the neurotrophin Trk receptors. Primary cortical neurons were treated with amitriptyline, nortriptyline and NGF and tested for neuronal complexity by Sholl analysis, protein expression by Western immunoblotting, and synapse number by colocalization of pre and postsynaptic makers. Amitriptyline (500 nmol/L) and its active metabolite nortriptyline (50 nmol/L) are found to induce neurite outgrowth in rat primary cortical neurons. Amitriptyline-induced neurite outgrowth is blocked by inhibition of Trk signaling using Trk antagonist K252a (200 nmol/L) but not by the neurotrophin inhibitor Y1036 (40 mumol/L), indicating that amitriptyline binds directly to the Trk receptor to initiate neurite outgrowth. MEK inhibitor PD98059 (10 mumol/L) also blocks amitriptyline-induced neurite outgrowth, implicating activation of the MAPK signaling pathway downstream of Trk receptor activation. Furthermore, pretreatment of primary cortical neurons with amitriptyline and nortriptyline prevents the effects of the proinflammatory cytokine TNF-alpha (10 ng/mL) on neurite outgrowth and colocalization of synaptic proteins. These findings suggest that amitriptyline and nortriptyline can exert neurotrophic effects in primary cortical neurons via activation of a Trk/MAPK signaling pathway. These compounds therefore have significant potential to be used in the treatment of neurodegenerative conditions where atrophy and loss of synaptic connections contribute to progression of disease.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amitriptyline	BDNF/NT-3 growth factors receptor	Protein	Humans	Unknown	Agonist	Details