TABLE 2.

Molecular targets of fingolimod and its relevant effective concentrations/doses.

Author/Year	Model/Therapeutic dose	Molecular target/Form	Effect	Mechanisms of action
Chiba 1998	Rats	-	Decreases Circulating Lymphocytes	Lymphocyte homing acceleration
Chiba et al. (1998)	0.1–1 mg/kg oral
Mandala 2002	Mice and Rats	S1P receptors/Phosphorylated	Rapid peripheral lymphopenia	Lymphocytes sequestration
Mandala et al. (2002)	2.5 mg/kg IV
Brinkmann 2002	Rats	S1P receptors	Decreases Circulating Lymphocytes	Lymphocytes sequestration in secondary lymphatic tissues and away from inflammatory lesions and graft sites
Brinkmann et al. (2002)	0.1–1 mg/kg oral	(1,3–5)/Phosphorylated
Sanchez 2003	Mice	S1P receptors/Phosphorylated	Decrease in VEGF-induced vascular permeability, maintains the integrity and functionality of endothelial cells	stimulates VE-cadherin and ß-catenin translocation and assembly into cell-cell junctions
Sanchez et al. (2003)	50 µg by gavage
Matloubian 2004	Mice	S1P1/Phosphorylated	Lymphopenia	S1P1 downregulation
Matloubian et al. (2004)	1.1 or 1 mg/kg IP
Bandhuvula 2005	Mice	S1P lyase/Non- Phosphorylated	Lymphopenia	S1P lyase inhibition
Bandhuvula et al. (2005)	1 mg IP
Lamontagne 2006	Mice	S1P1/Phosphorylated	Inhibition of tumor-associated angiogenesis	S1P1 internalization
LaMontagne et al. (2006)	0.3 or 3 mg/kg oral
Payne 2007	In vitro	cPLA2α/Non- Phosphorylated	Inflammation inhibition	cPLA2α inhibition
Payne et al. (2007)	200–800 p.m.
Schmid 2007	Mice	S1P1/Phosphorylated	Inhibition of tumor-associated angiogenesis
Schmid et al. (2007)	10 mg/kg IP
Toneli2010	In vitro	SK1/Non-Phosphorylated	Induces apoptosis in cancer cells	ubiquitin-proteasomal degradation
Tonelli et al. (2010)	50 µM
Lahiri 2009	In vitro	Ceramide synthase/Non-Phosphorylated	-	noncompetitive inhibition toward acyl-CoA and sphinganine
Lahiri et al. (2009)	25–100 µM
Chen 2013	Rats	Ceramide synthase/Non-Phosphorylated	Protects retina from light-induce degeneration	De novo Ceramide synthase inhibition
Chen et al. (2013)	10 mg/kg IP
Dawson 2011	In vitro	ASMase/Non-Phosphorylated	-	proteolytic degradation of the enzyme complex
Dawson and Qin, (2011)	10 µM
Hait 2014	In vitro	class I HDACs/Phosphorylated	facilitates fear extinction memory reactivates ERα expression	Binding to active site of class I HDACs leading to enzymatic activity inhibition
Hait et al. (2014)	5 µM
Hait 2015	Mice
Hait et al. (2015)	1 mg/kg oral
Segura-Ulate 2017	In vitro	HDAC/-	reverses a-synuclein-induced downregulation of BDNF	increased histone 3 acetylation
Segura-Ulate et al. (2017)	150 nM
Perla 2020	In vitro	HDAC/-	induces antitumor activities in medulloblastoma cells	increased histone 3 acetylation
Perla et al. (2020)	7.5 or 10 µM
Ji 2019	Rat	HDAC/Phosphorylated	M1 to M2 shift decrease pro-inflammatory factors prevent ischemia-induced brain injury	prevents KLF4 to interact with HDAC1
Ji et al. (2019)	2 mg/kg IP
Qin 2013	In vitro	TRPM7/Non-Phosphorylated	inhibits cell proliferation and migration	TRPM7 inhibition
Qin et al. (2013)	1 µM
Schilling 2014	In vitro	TRPM7/-	inhibits cell proliferation and polarization of macrophages	TRPM7 inhibition
Schilling et al. (2014)	3 µM
Van meeteren 2008	In vitro	Autotaxin/LPA axis/Phosphorylated	reduces plasma levels of LPA	Autotaxin inhibition
van Meeteren et al. (2008)	100–250 nM
	Mice
Szepanowski 2016	1 mg/kg oral
	Mice
Szepanowski et al. (2016)	1 mg/kg IP	Phosphorylated	LPA reduction	LPA synthesis inhibition
Matouska 2003	In vitro	PP2A/Non-Phosphorylated	Akt and p70S6k/p85S6k dephosphorylation leading to cell apoptosis	disruption of interaction of PP2A to SET, leading to PP2A activation
Matsuoka et al. (2003)	2.5–10 µM