TLR4 and amyotrophic lateral sclerosis: new aPEAling role for palmitoylethanolamide?
jan keppel hesselink, institute neuropathic pain
19 May 2015
In the thought-provoking article of Lee and colleagues, the pathogenetic role of the toll-like receptor 4 is elegantly shown in a mouse model for ALS.
It is worthwhile to point out that the natural anti-inflammatory compound palmitoylethanolamide has TLR4 antagonistic properties, as shown in inflammation models of colitis ulcerosa. (Esposito et al, 2014)
This fact provoked the comment of McKernan et al, bearing the title: "An apPEAling new therapeutic for ulcerative colitis?"In addition to this, the FAAH inhibitor URB597 increased hippocampal levels of the N-acylethanolamines such as palmitoylethanolamide and attenuated TLR3-induced IL-1β and TNFα expression, thus reducing TLR3-induced neuroinflammatory responses. (Henry et al, 2014)
Palmitoylethanolamide is a very special supplement, easily available and easy to titrate in the clinic, due to its very benign side-effect profile. Doses up to 100 mg/kg BW in humans can be administered without dose-limiting side effects.
Isolated cases of patients suffering from ALS have been published, were palmitoylethanolamide decreased various symptoms, such as the muscle weakness. (Clemente, 2012)
In the web many report of patients suffering from ALS (rather Charcot's disease than Lou-Gehring disease, as Charcot initially described this neuroinflammatory disorder) can be found reporting positive effects of palmitoylethanolamide.
The article of Lee et al should therefore attrackt the attention of neurologists, especially since in ALS no relevant therapy has yet been found (riluzole is only marginally effective), and recent phase III trials, on the base of promising phase II trial results, sadly enough were negative. (Cudkowicz et al, 2015; Lenglet et al, 2014)
We recommend to dose palmitoylethanolamide quite high, 2400 mg/daily for at least 2-3 months, before coming to a clinical judgment wether there is a meaningful effect. For palmitoylethanolamide clinicians do not need to fear dose-limiting side-effects.
References
Clemente S. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report. CNS Neurol Disord Drug Targets. 2012 Nov 1;11(7):933-6.
Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, Hayden D, Shui A, Brooks B, Conwit R, Felsenstein D, Greenblatt DJ, Keroack M, Kissel JT, Miller R, Rosenfeld J, Rothstein JD, Simpson E, Tolkoff-Rubin N, Zinman L, Shefner JM; Ceftriaxone Study Investigators. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 Nov;13(11):1083-91. doi: 10.1016/S1474-4422(14)70222-4. Epub 2014 Oct 5.
Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation.L. Gut. 2014 Aug;63(8):1300-12. doi: 10.1136/gutjnl-2013-305005. Epub 2013 Sep 30.
Henry RJ, Kerr DM, Finn DP, Roche M.J. FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus. Neuroimmunol. 2014 Nov 15;276(1-2):126-34. doi: 10.1016/j.jneuroim.2014.09.002. Epub 2014 Sep 16.
McKernan DP, Finn DP. An apPEAling new therapeutic for ulcerative colitis? Gut. 2014 Aug;63(8):1207-8. doi: 10.1136/gutjnl-2013-305929. Epub 2013 Oct 23.
Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, Shaw PJ, Pruss RM, Cuvier V, Meininger V; Mitotarget study group. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis.Eur J Neurol. 2014 Mar;21(3):529-36. doi: 10.1111/ene.12344. Epub 2014 Jan 21.
Journal of Neuroinflammation
TLR4 and amyotrophic lateral sclerosis: new aPEAling role for palmitoylethanolamide?
19 May 2015
In the thought-provoking article of Lee and colleagues, the pathogenetic role of the toll-like receptor 4 is elegantly shown in a mouse model for ALS.
It is worthwhile to point out that the natural anti-inflammatory compound palmitoylethanolamide has TLR4 antagonistic properties, as shown in inflammation models of colitis ulcerosa. (Esposito et al, 2014)
This fact provoked the comment of McKernan et al, bearing the title: "An apPEAling new therapeutic for ulcerative colitis?"In addition to this, the FAAH inhibitor URB597 increased hippocampal levels of the N-acylethanolamines such as palmitoylethanolamide and attenuated TLR3-induced IL-1β and TNFα expression, thus reducing TLR3-induced neuroinflammatory responses. (Henry et al, 2014)
Palmitoylethanolamide is a very special supplement, easily available and easy to titrate in the clinic, due to its very benign side-effect profile. Doses up to 100 mg/kg BW in humans can be administered without dose-limiting side effects.
Isolated cases of patients suffering from ALS have been published, were palmitoylethanolamide decreased various symptoms, such as the muscle weakness. (Clemente, 2012)
In the web many report of patients suffering from ALS (rather Charcot's disease than Lou-Gehring disease, as Charcot initially described this neuroinflammatory disorder) can be found reporting positive effects of palmitoylethanolamide.
The article of Lee et al should therefore attrackt the attention of neurologists, especially since in ALS no relevant therapy has yet been found (riluzole is only marginally effective), and recent phase III trials, on the base of promising phase II trial results, sadly enough were negative. (Cudkowicz et al, 2015; Lenglet et al, 2014)
We recommend to dose palmitoylethanolamide quite high, 2400 mg/daily for at least 2-3 months, before coming to a clinical judgment wether there is a meaningful effect. For palmitoylethanolamide clinicians do not need to fear dose-limiting side-effects.
References
Clemente S. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report. CNS Neurol Disord Drug Targets. 2012 Nov 1;11(7):933-6.
Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, Hayden D, Shui A, Brooks B, Conwit R, Felsenstein D, Greenblatt DJ, Keroack M, Kissel JT, Miller R, Rosenfeld J, Rothstein JD, Simpson E, Tolkoff-Rubin N, Zinman L, Shefner JM; Ceftriaxone Study Investigators. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 Nov;13(11):1083-91. doi: 10.1016/S1474-4422(14)70222-4. Epub 2014 Oct 5.
Esposito G, Capoccia E, Turco F, Palumbo I, Lu J, Steardo A, Cuomo R, Sarnelli G, Steardo. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation.L. Gut. 2014 Aug;63(8):1300-12. doi: 10.1136/gutjnl-2013-305005. Epub 2013 Sep 30.
Henry RJ, Kerr DM, Finn DP, Roche M.J. FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus. Neuroimmunol. 2014 Nov 15;276(1-2):126-34. doi: 10.1016/j.jneuroim.2014.09.002. Epub 2014 Sep 16.
McKernan DP, Finn DP. An apPEAling new therapeutic for ulcerative colitis? Gut. 2014 Aug;63(8):1207-8. doi: 10.1136/gutjnl-2013-305929. Epub 2013 Oct 23.
Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, Shaw PJ, Pruss RM, Cuvier V, Meininger V; Mitotarget study group. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis.Eur J Neurol. 2014 Mar;21(3):529-36. doi: 10.1111/ene.12344. Epub 2014 Jan 21.
Competing interests
No competing interest