Idebenone

    Researchedby:
    Kamal Patel
    Last Updated: September 28, 2022

    Idebenone (CV-2619) is a synthetic derivative of CoQ10 that appears to retain the antioxidative and bioenergetic effects of its parent compound. It appears to be useful in certain disease states.

    Idebenone is most often used for



    1.

    Sources and Structure

    1.1

    Sources

    Idebenone (full structural name of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone and codename of-2619[1]) is a synthetic derivative of ubiquinone (reduced CoQ10).

    2.

    Pharmacology

    2.1

    Serum

    A preliminary test using 150mg Idebenone in two healthy males noted that, after one hour, serum concentrations reached 422.8ng/mL.[2]

    2.2

    Metabolism

    Idebenone can be reduced, and the reduced form subsequently oxidized via cytochrome B of the electron transport chain.[3] The reduced form appears to be the one that mediates anti-lipid peroxidative effects.[1]

    3.

    Neurology

    3.1

    Mechanisms

    Idebenone (particularly its reduced form) is highly antioxidative, with IC50 values against oxidative damage in the range of 0.5-10µM.[1]

    3.2

    Glutaminergic Neurotransmission

    In vitro, Idebenone can reduce glutamate-induced toxicity in the range of 0.1-3µM secondary to its antioxidative properties,[4] and at a potency exceeding Vitamin E (requiring 10-100µM) and Vinpocetine (10-100µM).[4] It also appears effective against excitotoxicity associated with ATP depletion (independent of NMDA receptors, but still from glutamate[5]) secondary to its antioxidative effects.[5][6]

    Unlike many other compounds, Idebenone appears to be protective against excitotoxicity mediated via the AMPA and kainate receptors but not NMDA[7] although some general neuroprotection from the antioxidative effects may persist on NMDA (as noted elsewhere).[8]

    Ischemia (damaging via glutamate) appears to be protected against with idebenone (100mg/kg intraperitoneal injections)[9] and secondary to that a preservation of memory (losses seen with ischemic control).[10]

    In periods of excitotoxicity, idebenone appears to exert a protective effect. This is mostly due to the antioxidative effects preventing ATP depletion

    50μM idebenone can suppress 4-AP induced glutamate release without affecting basal glutamate release and as this is inhibited by bafilomycin A1 it is thought to be due to reducing exocytosis of glutamate; this was dependent on calcium ions, and mostly CaV2.2 and CaV2.1 channels.[11]

    Glutamate release appears to be suppressed with idebenone supplementation, and this suppression is due to less synaptic release of glutamate containing vesicles rather than anything at the level of the synapse

    Although idebenone has once failed to alter synaptic sensitivity to glutamate[11] it has elsewhere at 10-100μM been found to enhance signalling via AMPA receptors (those comprising α1 and α2 subunits).[12]

    Although it is possible that Idebenone can enhance glutaminergic signalling, there is mixed evidence right now and no in vivo studies to confirm

    3.3

    Memory and Learning

    Impairments (via age or injury) in passive avoidance retention, working memory, and delayed alternation can be reduced or reversed by pretraining administration of 3-30mg/kg idebenone[13][14][15][10] For acute usage, 30mg/kg appears to be optimal when injected (intraperitoneal)[15] whereas 3mg/kg injections are sufficient for chronic studies.[16]

    3.4

    Alzheimer& #039;s

    Idebenone has been found to be neuroprotective against β-amyloid peptides[17] which is thought to be related to the antioxidative properties of idebenone (as antioxidants, per se, are neuroprotective).[18] These protective effects have been confirmed in vivo as assessed by a reduction in memory loss.[19]

    4.

    Interactions with Organ Systems

    4.1

    Eyes

    Leber’s hereditary optic neuropathy (LHON) has been noted to have remission associated with idebenone supplementation[20] and/or accelerate the rate of recovery,[21] with other case studies, open-label trials, or retrospective assessments noting benefit with supplementation.[22][23][24][25][26] It has since been investigated in a 24 week trial where 900mg of idebenone daily was able to improve visual acuity only in those with discordant visual acuities at baseline.[27]

    May have benefit for visual acuity in Leber’s hereditary optic neuropathy at a dosage of around 900mg daily (lower doses may be effective, but to a lesser degree)

    References

    1. ^Suno M, Nagaoka AInhibition of lipid peroxidation by a novel compound (CV-2619) in brain mitochondria and mode of action of the inhibitionBiochem Biophys Res Commun.(1984 Dec 28)
    2. ^Nohara Y, Suzuki J, Yamazaki Y, Kubo HDetermination of idebenone in plasma by HPLC with post-column fluorescence derivatization using 2-cyanoacetamideChem Pharm Bull (Tokyo).(2012)
    3. ^Sugiyama Y, Fujita T, Matsumoto M, Okamoto K, Imada IEffects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogsJ Pharmacobiodyn.(1985 Dec)
    4. ^Miyamoto M, Murphy TH, Schnaar RL, Coyle JTAntioxidants protect against glutamate-induced cytotoxicity in a neuronal cell lineJ Pharmacol Exp Ther.(1989 Sep)
    5. ^Pereira CM, Oliveira CRGlutamate toxicity on a PC12 cell line involves glutathione (GSH) depletion and oxidative stressFree Radic Biol Med.(1997)
    6. ^Pereira C, Santos MS, Oliveira CMetabolic inhibition increases glutamate susceptibility on a PC12 cell lineJ Neurosci Res.(1998 Feb 1)
    7. ^Miyamoto M, Coyle JTIdebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxinsExp Neurol.(1990 Apr)
    8. ^Bruno V, Battaglia G, Copani A, Sortino MA, Canonico PL, Nicoletti FProtective action of idebenone against excitotoxic degeneration in cultured cortical neuronsNeurosci Lett.(1994 Sep 12)
    9. ^Nagaoka A, Suno M, Shibota M, Kakihana MEffects of idebenone on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemiaArch Gerontol Geriatr.(1989 May)
    10. ^Yamazaki N, Kiyota Y, Take Y, Miyamoto M, Nagawa Y, Nagaoka AEffects of idebenone on memory impairment induced in ischemic and embolization models of cerebrovascular disturbance in ratsArch Gerontol Geriatr.(1989 May)
    11. ^Chang Y, Lin YW, Wang SJIdebenone inhibition of glutamate release from rat cerebral cortex nerve endings by suppression of voltage-dependent calcium influx and protein kinase ANaunyn Schmiedebergs Arch Pharmacol.(2011 Jul)
    12. ^Nakamura S, Kaneko S, Satoh MPotentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective glutamate receptor function by a nootropic drug, idebenoneBiol Pharm Bull.(1994 Jan)
    13. ^Karasawa Y, Araki H, Okuyama S, Aihara H, Otomo SEffect of minaprine and other reference drugs on passive avoidance impairment induced by cerebral ischemia in Mongolian gerbilsJpn J Pharmacol.(1990 Jul)
    14. ^Kiyota Y, Hamajo K, Miyamoto M, Nagaoka AEffect of idebenone (CV-2619) on memory impairment observed in passive avoidance task in rats with cerebral embolizationJpn J Pharmacol.(1985 Mar)
    15. ^Beneficial effects of idebenone on memory impairment in rats
    16. ^Pelleymounter MA, Cullen MJEffects of idebenone on information processing in aged Long-Evans ratsPharmacol Biochem Behav.(1993 Oct)
    17. ^Hirai K, Hayako H, Kato K, Miyamoto MIdebenone protects hippocampal neurons against amyloid beta-peptide-induced neurotoxicity in rat primary culturesNaunyn Schmiedebergs Arch Pharmacol.(1998 Nov)
    18. ^Pereira C, Santos MS, Oliveira CInvolvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidantsNeurobiol Dis.(1999 Jun)
    19. ^Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima TProtective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivoEur J Neurosci.(1999 Jan)
    20. ^Mashima Y, Hiida Y, Oguchi YRemission of Leber's hereditary optic neuropathy with idebenoneLancet.(1992 Aug 8)
    21. ^Mashima Y, Kigasawa K, Wakakura M, Oguchi YDo idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathyJ Neuroophthalmol.(2000 Sep)
    22. ^Cortelli P, Montagna P, Pierangeli G, Lodi R, Barboni P, Liguori R, Carelli V, Iotti S, Zaniol P, Lugaresi E, Barbiroli BClinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS studyJ Neurol Sci.(1997 May 1)
    23. ^Carelli V, Barboni P, Zacchini A, Mancini R, Monari L, Cevoli S, Liguori R, Sensi M, Lugaresi E, Montagna PLeber's Hereditary Optic Neuropathy (LHON) with 14484/ND6 mutation in a North African patientJ Neurol Sci.(1998 Oct 8)
    24. ^Carelli V, Valentino ML, Liguori R, Meletti S, Vetrugno R, Provini F, Mancardi GL, Bandini F, Baruzzi A, Montagna PLeber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two casesJ Neurol Neurosurg Psychiatry.(2001 Dec)
    25. ^Barnils N, Mesa E, Muñoz S, Ferrer-Artola A, Arruga JResponse to idebenone and multivitamin therapy in Leber's hereditary optic neuropathyArch Soc Esp Oftalmol.(2007 Jun)
    26. ^Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni PIdebenone treatment in Leber's hereditary optic neuropathyBrain.(2011 Sep)
    27. ^Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PFA randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathyBrain.(2011 Sep)