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Pleiotropic neuroprotective and metabolic effects of Actovegin's mode of action

Published:August 20, 2012DOI:https://doi.org/10.1016/j.jns.2012.07.069

      Abstract

      This article reviews the mechanisms of action of Actovegin in the context of its preclinical effects and new concepts in the pharmacological treatment of neurological disorders. Actovegin is an ultrafiltrate of calf blood, composed of more than 200 biological substances. The drug is used for a broad spectrum of diseases, including disturbances of peripheral and cerebral blood circulation, burns, impaired wound healing, radiation-induced damage and diabetic polyneuropathy. Actovegin is composed of small molecules present under normal physiological conditions, therefore pharmacokinetic and pharmacodynamic studies to determine its active substance are not feasible. Preclinical data have revealed that it improves metabolic balance by increasing glucose uptake and improving oxygen uptake under conditions of ischemia. Actovegin also resists the effects of gamma-irradiation and stimulates wound healing. More recent preclinical studies have suggested that anti-oxidative and anti-apoptotic mechanisms of action specifically underlie the neuroprotective properties of Actovegin. The drug has been found to exert these beneficial effects experimentally, in primary rat hippocampal neurons and in an STZ-rat model of diabetic polyneuropathy, while also providing evidence that it positively affects the functional recovery of neurons. Latest data suggest that Actovegin also has a positive influence on the NF-κB pathway, but many molecular and cellular pathways remain unexplored. In particular, Actovegin's influence on neuroplasticity, neurogenesis and neurotrophicity are questions that ideally should be answered by future research. Nevertheless, it is clear that the multifactorial and complex nature of Actovegin underlies its pleiotropic neuroprotective mechanisms of action and positive effect on clinical outcomes.

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      References

        • Muresanu D.F.
        Neuromodulation with pleiotropic and multimodal drugs — future approaches to treatment of neurological disorders.
        Acta Neurochir Suppl. 2010; 106: 291-294
        • Labiche L.A.
        • Grotta J.C.
        Clinical trials for cytoprotection in stroke.
        NeuroRx. Jan. 2004; 1: 46-70
        • Maas A.I.
        • Roozenbeek B.
        • Manley G.T.
        Clinical trials in traumatic brain injury: past experience and current developments.
        Neurotherapeutics. 2010 Jan; 7: 115-126
        • Bornstein N.M.
        Stroke: practical guide for physicians.
        S. Karger AG, 2009
        • Muresanu D.F.
        Neuroprotection and neuroplasticity — a holistic approach and future perspectives.
        J Neurol Sci. 2007 Jun 15; 257: 38-43
        • Mochida H.
        • Kikuchi T.
        • Tanaka H.
        • Ikeda A.
        • Fujii Y.
        • Sasamura T.
        • et al.
        Influence of Actovegin containing infusion solutions on wound healing and function of the intestinal tract in rats.
        Pharmacol Ther. 1989; 17: 789-797
        • Schonwald D.
        • Sixt B.
        • Machicao F.
        • Marx E.
        • Haedenkamp G.
        • Bertsch S.
        Enhanced proliferation of coronary endothelial cells in response to growth factors is synergized by hemodialysate compounds in vitro.
        Res Exp Med (Berl). 1991; 191: 259-272
        • Basu S.K.
        • Srinivasan M.N.
        • Chuttani K.
        • Ghose A.
        Evaluation of some radioprotectors by the survival study of rats exposed to lethal dose of whole body gamma radiation.
        J Radiat Res (Tokyo). 1985 Dec; 26: 395-403
        • Hegner N.
        Wirkung eines deproteinisierten Hämoderivates (Actovegin) im induzierten hypovolämischen Schock unter besonderen Berücksichtigung des Energiestoffwechsels.
        Institut für Anästhesiologie, Johannes-Gutenberg Universität Mainz1983
        • Giarola P.
        Effects of blood extract on plasma lipids, blood coagulation, fibrinolysis, and platelet aggregation in experimental hypercholesterolemia of rabbits.
        Arzneim-Forsch. 1974; 24: 925-928
        • Elmlinger M.W.
        • Kriebel M.
        • Ziegler D.
        Neuroprotective and anti-oxidative effects of the hemodialysate actovegin on primary rat neurons in vitro.
        Neuromolecular Med. 2011 Dec; 13: 266-274
        • Dieckmann A.
        • Kriebel M.
        • Andriambeloson E.
        • Ziegler D.
        • Elmlinger M.
        Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation.
        Exp Clin Endocrinol Diabetes. 2011 Oct 21; 120: 132-138
        • Kuninaka T.
        • Senga Y.
        • Senga H.
        • Weiner M.
        Nature of enhanced mitochondrial oxidative metabolism by a calf blood extract.
        J Cell Physiol. 1991 Jan; 146: 148-155
        • Buchmayer F.
        • Pleiner J.
        • Elmlinger M.W.
        • Lauer G.
        • Nell G.
        • Sitte H.H.
        Actovegin®: a biological drug for more than 5 decades.
        Wien Med Wochenschr. 2011 Feb; 161: 80-88
        • Bachmann W.
        • Forster H.
        • Mehnert H.
        Experimental studies in animals on the effect of a protein-free blood extract on the metabolism of glucose.
        Arzneim-Forsch. 1968; 18: 1023-1027
        • Rao J.
        • Oz G.
        • Seaquist E.R.
        Regulation of cerebral glucose metabolism.
        Minerva Endocrinol. 2006 Jun; 31: 149-158
        • McEwen B.S.
        • Reagan L.P.
        Glucose transporter expression in the central nervous system: relationship to synaptic function.
        Eur J Pharmacol. 2004 Apr 19; 490: 13-24
        • Grillo C.A.
        • Piroli G.G.
        • Hendry R.M.
        • Reagan L.P.
        Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent.
        Brain Res. 2009 Nov 3; 1296: 35-45
        • Kobayashi M.
        • Nikami H.
        • Morimatsu M.
        • Saito M.
        Expression and localization of insulin-regulatable glucose transporter (GLUT4) in rat brain.
        Neurosci Lett. 1996 Aug 2; 213: 103-106
        • Pardridge W.M.
        • Oldendorf W.H.
        • Cancilla P.
        • Frank H.J.
        Blood–brain barrier: interface between internal medicine and the brain.
        Ann Intern Med. 1986 Jul; 105: 82-95
        • Zhao W.Q.
        • Chen H.
        • Quon M.J.
        • Alkon D.L.
        Insulin and the insulin receptor in experimental models of learning and memory.
        Eur J Pharmacol. 2004 Apr 19; 490: 71-81
        • Nitsch R.
        • Hoyer S.
        Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex.
        Neurosci Lett. 1991 Jul 22; 128: 199-202
        • Ding A.
        • Nemeth G.
        • Hoyer S.
        Age influences abnormalities in striatal dopamine metabolism during and after transient forebrain ischemia.
        J Neural Transm Park Dis Dement Sect. 1992; 4: 213-225
        • Lannert H.
        • Hoyer S.
        Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats.
        Behav Neurosci. 1998 Oct; 112: 1199-1208
        • Salkovic-Petrisic M.
        • Hoyer S.
        Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach.
        J Neural Transm Suppl. 2007; 72: 217-233
        • Machicao F.
        • Mühlbacher C.
        • Haring H.
        Inositol phospho-oligosaccharides from a dialysate (Actovegin) obtained from blood mimic the effect of lipogenesis glucose transport and lipolysis in rat adipocytes.
        Akt Endokr Stoffw. 1989; 10: 111
        • Kellerer M.
        • Machicao F.
        • Berti L.
        • Sixt B.
        • Mushack J.
        • Seffer E.
        • et al.
        Inositol phospho-oligosaccharides from rat fibroblasts and adipocytes stimulate 3-O-methylglucose transport.
        Biochem J. 1993 Nov 1; 295: 699-704
        • Reichel H.
        • Weiss C.
        • Leichtweiss H.P.
        The effects of a blood extract on the oxygen uptake of isolated artificially perfused kidneys and skeletal muscles in rats.
        Arzneim-Forsch. 1965; 15: 757
        • de Groot H.
        • Brecht M.
        • Machicao F.
        Evidence for a factor protective against hypoxic liver parenchymal cell injury in a protein-free blood extract.
        Res Commun Chem Pathol Pharmacol. Apr. 1990; 68: 125-128
        • Hoyer S.
        • Betz K.
        Elimination of the delayed postischemic energy deficit in cerebral cortex and hippocampus of aged rats with a dried, deproteinized blood extract (Actovegin).
        Arch Gerontol Geriatr. 1989 Sep; 9: 181-192
        • Murakami K.
        • Shimizu T.
        • Irie K.
        Formation of the 42-mer amyloid beta radical and the therapeutic role of superoxide dismutase in Alzheimer's disease.
        J. Amino Acids. 2011; 2011: 654207
        • Zhang X.H.
        • Yu H.L.
        • Xiao R.
        • Xiang L.
        • Li L.
        • Ma W.W.
        • et al.
        Neurotoxicity of beta-amyloid peptide 31–35 and 25–35 to cultured rat cortical neurons.
        Zhonghua Yu Fang Yi Xue Za Zhi. 2009 Dec; 43: 1081-1085
        • Pike C.J.
        • Walencewicz-Wasserman A.J.
        • Kosmoski J.
        • Cribbs D.H.
        • Glabe C.G.
        • Cotman C.W.
        Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity.
        J Neurochem. 1995 Jan; 64: 253-265
        • Millucci L.
        • Raggiaschi R.
        • Franceschini D.
        • Terstappen G.
        • Santucci A.
        Rapid aggregation and assembly in aqueous solution of A beta (25–35) peptide.
        J Biosci. 2009 Jun; 34: 293-303
        • Trubetskaya V.V.
        • Stepanichev M.Y.
        • Onufriev M.V.
        • Lazareva N.A.
        • Markevich V.A.
        • Gulyaeva N.V.
        Administration of aggregated beta-amyloid peptide (25–35) induces changes in long-term potentiation in the hippocampus in vivo.
        Neurosci Behav Physiol. 2003 Feb; 33: 95-98
        • Klementiev B.
        • Novikova T.
        • Novitskaya V.
        • Walmod P.S.
        • Dmytriyeva O.
        • Pakkenberg B.
        • et al.
        A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25–35.
        Neuroscience. 2007 Mar 2; 145: 209-224
        • Kubo T.
        • Nishimura S.
        • Kumagae Y.
        • Kaneko I.
        In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1–40) to truncated and toxic fragments ([D-Ser 26]A beta 25–35/40) and fragment presence in the brains of Alzheimer's patients.
        J Neurosci Res. 2002 Nov 1; 70: 474-483
        • Meffert M.K.
        • Chang J.M.
        • Wiltgen B.J.
        • Fanselow M.S.
        • Baltimore D.
        NF-kappa B functions in synaptic signaling and behavior.
        Nat Neurosci. 2003 Oct; 6: 1072-1078
        • Kaltschmidt B.
        • Kaltschmidt C.
        NF-kappaB in the nervous system.
        Cold Spring Harb Perspect Biol. 2009 Sep; 1: a001271
        • Kaltschmidt B.
        • Uherek M.
        • Wellmann H.
        • Volk B.
        • Kaltschmidt C.
        Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis.
        Proc Natl Acad Sci U S A. 1999 Aug 3; 96: 9409-9414
        • Meunier A.
        • Latremoliere A.
        • Dominguez E.
        • Mauborgne A.
        • Philippe S.
        • Hamon M.
        • et al.
        Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.
        Mol Ther. 2007 Apr; 15: 687-697
        • Mattson M.P.
        • Meffert M.K.
        Roles for NF-kappaB in nerve cell survival, plasticity, and disease.
        Cell Death Differ. 2006 May; 13: 852-860
        • Tamatani M.
        • Che Y.H.
        • Matsuzaki H.
        • Ogawa S.
        • Okado H.
        • Miyake S.
        • et al.
        Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons.
        J Biol Chem. 1999 Mar 26; 274: 8531-8538
        • Kenchappa P.
        • Yadav A.
        • Singh G.
        • Nandana S.
        • Banerjee K.
        Rescue of TNFalpha-inhibited neuronal cells by IGF-1 involves Akt and c-Jun N-terminal kinases.
        J Neurosci Res. 2004 May 15; 76: 466-474
        • Waetzig G.H.
        • Rosenstiel P.
        • Arlt A.
        • Till A.
        • Brautigam K.
        • Schafer H.
        • et al.
        Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1.
        FASEB J. 2005 Jan; 19: 91-93
        • Nawashiro H.
        • Tasaki K.
        • Ruetzler C.A.
        • Hallenbeck J.M.
        TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice.
        J Cereb Blood Flow Metab. 1997 May; 17: 483-490
        • Bruce A.J.
        • Boling W.
        • Kindy M.S.
        • Peschon J.
        • Kraemer P.J.
        • Carpenter M.K.
        • et al.
        Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors.
        Nat Med. 1996 Jul; 2: 788-794
        • Arnett H.A.
        • Mason J.
        • Marino M.
        • Suzuki K.
        • Matsushima G.K.
        • Ting J.P.
        TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination.
        Nat Neurosci. 2001 Nov; 4: 1116-1122
        • Barger S.W.
        • Horster D.
        • Furukawa K.
        • Goodman Y.
        • Krieglstein J.
        • Mattson M.P.
        Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation.
        Proc Natl Acad Sci U S A. 1995 Sep 26; 92: 9328-9332
        • Kaltschmidt C.
        • Kaltschmidt B.
        • Neumann H.
        • Wekerle H.
        • Baeuerle P.A.
        Constitutive NF-kappa B activity in neurons.
        Mol Cell Biol. 1994 Jun; 14: 3981-3992
        • Pieper A.A.
        • Verma A.
        • Zhang J.
        • Snyder S.H.
        Poly (ADP-ribose) polymerase, nitric oxide and cell death.
        Trends Pharmacol Sci. 1999 Apr; 20: 171-181
        • Eliasson M.J.
        • Sampei K.
        • Mandir A.S.
        • Hurn P.D.
        • Traystman R.J.
        • Bao J.
        • et al.
        Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.
        Nat Med. 1997 Oct; 3: 1089-1095
        • Burkart V.
        • Wang Z.Q.
        • Radons J.
        • Heller B.
        • Herceg Z.
        • Stingl L.
        • et al.
        Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin.
        Nat Med. 1999 Mar; 5: 314-319
        • Pieper A.A.
        • Brat D.J.
        • Krug D.K.
        • Watkins C.C.
        • Gupta A.
        • Blackshaw S.
        • et al.
        Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes.
        Proc Natl Acad Sci U S A. 1999 Mar 16; 96: 3059-3064
        • Garcia S.F.
        • Virag L.
        • Jagtap P.
        • Szabo E.
        • Mabley J.G.
        • Liaudet L.
        • et al.
        Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation.
        Nat Med. 2001 Jan; 7: 108-113
        • Ilnytska O.
        • Lyzogubov V.V.
        • Stevens M.J.
        • Drel V.R.
        • Mashtalir N.
        • Pacher P.
        • et al.
        Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy.
        Diabetes. 2006 Jun; 55: 1686-1694