Table 2 Mechanisms of action: latrepirdine
Cellular target/pathway | Drug activity | Reference |
|---|---|---|
Ion channels and receptor activity | Inhibits voltage-gated calcium channels Interacts with L-type Ca2+ channel, sodium channel, hERG potassium channel and transporter for norepinephrine Blocks histamine receptor (H1 and H2) activity Inhibits NMDA receptors and potentiates activity of AMPA-receptors Inhibits α-adrenergic receptors (α1A, α1B, α1D, and α2A), imidazoline I2 receptor and serotonin 5-HT2c, 5-HT5A, 5-HT6 receptors | |
Mitochondrial activity | Modulate the mitochondrial PTP and suppresses opening of PTP induced by neurotoxins Attenuates Ca2+-induced mitochondrial swelling Improves mitochondrial function on aspects such as mitochondrial membrane potential and ATP synthesis Protects mitochondrial membrane integrity Enhanced CGU in aged mice Restore the toxic effects of Aβ on mitochondrial morphology, respiratory chain complex and enlarged mitochondrial mass | |
Protein aggregation | Reduces the number of TDP-43 aggregates in neuroblastoma cells Reduces the number of amyloid deposits in the spinal cord of over expressing γ-synuclein mice Reduces accumulation of hippocampal/subicular APP/Aβ and α-synuclein in mice Elevates secretion of Aβ in the extracellular media in neuronal cells and AD transgenic mice Reduces GFP-Aβ42 in wild-type compared with the autophagy-deficient mutant (Atg8Δ) in yeast model | |
Protein degradation pathways | Upregulates autophagic markers in yeast model Enhances mTOR- and Atg5-dependent autophagy cultured mammalian cells Shows increased UPS activity in over expression γ-synuclein mice model | |
Neuroprotective functions | Inhibits MAO deaminating dopamine and serotonin, decrease dopamine metabolism and increase noradrenaline level in the rat brain Inhibits of both acetylcholine esterase and butyrylcholine esterase. Restores TWAA performance in rats injected with AF64A Prevents development of convulsions and death caused by NMDA induced toxicity in mice Reduces amphetamine induced striatal dopamine depletion in mice and promote hippocampus-dependent learning in both appetitive and inhibitory tasks in mice Enhance memory and learning in a primate model Increases hippocampal neurogenesis in the mouse model Reduces the development of motor dysfunction in overexpressing synuclein mice model Improves spatial memory function and behaviour in AD transgenic mice Protects cultured cells against Aβ toxicity |
