Abstract

Ibudilast (IBD) is a non-selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response) by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), toll-like receptor 4 blockade (TLR-4), inhibition of a macrophage migration inhibitory factor (MIF), up-regulation the anti-inflammatory cytokine (IL-10), and promotion of neurotrophic factors (GDNF, NGF, NT-4). Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood–brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub-optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors-mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.

References

• 1. A Phase 2 Randomized, Double‑blind, Placebo‑controlled Study to Evaluate the Safety, Tolerability and Activity of Ibudilast (MN‑166) in Subjects With Progressive Multiple Sclerosis. www.ClinicalTrials. gov. Identifier: NCT01982942 (27.08.2014)
  Google Scholar
• 2. A Prospective, Double‑Blind, Randomized, Placebo‑Controlled Trial of AV411to Assess Its Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy in the Treatment of Neuropathic Pain. www. ClinicalTrials.gov. Identifier: NCT00576277 (27.08.2014)
  Google Scholar
• 3. Barkhof F., Hulst H.E., Drulovic J., Uitdehaag B.M., Matsuda K., Landin r., MN166‑001 Investigators: Ibudilast in relapsing‑remitting multiple sclerosis: a neuroprotectant? Neurology, 2010; 74: 1033‑1040
  Google Scholar
• 4. Beardsley P.M., Shelton K.L., Hendrick E., Johnson K.W.: The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime – and stress‑induced methamphetamine relapse. Eur. J. Pharmacol., 2010; 637: 102‑108
  Google Scholar
• 5. Bell r.L., Lopez M.F., Cui C., Egli M., Johnson K.W., Franklin K.M., Becker H.C.: Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict. Biol., 2015; 20: 38‑42
  Google Scholar
• 6. Benbow J.H., Mann T., Keeler C., Fan C., Hodsdon M.E., Lolis E., DeGray B., Ehrlich B.E.: Inhibition of paclitaxel‑induced decreases in calcium signaling. J. Biol. Chem., 2012; 287: 37907‑37916
  Google Scholar
• 7. Bernhagen J., Krohn  r., Lue H., Gregory J.L., Zernecke A., Koenen r.R., Dewor M., Georgiev I., Schober A., Leng L., Kooistra T., Fingerle‑Rowson G., Ghezzi P., Kleemann r., McColl S.R., Bucala r., Hickey M.J., Weber C.: MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med., 2007; 13: 587‑596
  Google Scholar
• 8. Bora r.S., Gupta D., Malik r., Chachra S., Sharma P., Saini K.S.: De‑ velopment of a cell‑based assay for screening of phosphodiesterase 10A (PDE10A) inhibitors using a stable recombinant HEK‑293 cell line expressing high levels of PDE10A. Biotechnol. Appl. Biochem., 2008; 49: 129‑134
  Google Scholar
• 9. Bourtchouladze r., Lidge r., Catapano r., Stanley J., Gossweiler S., Romashko D., Scott r., Tully T.: A mouse model of Rubinstein‑Taybi syndrome: defective long‑term memory is ameliorated by inhibi‑ tors of phosphodiesterase 4. Proc. Natl. Acad. Sci. USA, 2003; 100: 10518‑10522
  Google Scholar
• 10. Calandra T., Roger T.: Macrophage migration inhibitory factor: a regulator of innate immunity. Nat. Rev. Immunol., 2003; 3: 791‑800
  Google Scholar
• 11. Chappie T., Humphrey J., Menniti F., Schmidt C.: PDE10A inhibitors: an assessment of the current CNS drug discovery landscape. Curr. Opin. Drug Discov. Devel., 2009; 12: 458‑467
  Google Scholar
• 12. Cho Y., Crichlow G.V., Vermeire J.J., Leng L., Du X., Hodsdon M.E., Bucala r., Cappello M., Gross M., Gaeta F., Johnson K., Lolis E.J.: Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast. Proc. Natl. Acad. Sci. USA, 2010; 107: 11313‑11318
  Google Scholar
• 13. Clark K.H., Wiley C.A., Bradberry C.W.: Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox. Res., 2013; 23: 174‑188
  Google Scholar
• 14. Collins S.D., Chessell I.P.: Emerging therapies for neuropathic pain. Expert Opin. Emerg. Drugs, 2005; 10: 95‑108
  Google Scholar
• 15. Deleo J.A., Tanga F.Y., Tawfik V.L.: Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist, 2004; 10: 40‑52
  Google Scholar
• 16. Development of Ibudilast as a Novel Treatment for Alcohol Dependence.www.ClinicalTrials.gov. Identifier: NCT02025998 (19.02.2016)
  Google Scholar
• 17. Effects of Ibudilast (MN‑166, Formerly AV411), a Glial Activation Inhibitor, on Oxycodone Self‑administration in Opioid Abusers. www.ClinicalTrials.gov. Identifier: NCT01740414 (27.08.2014)
  Google Scholar
• 18. Ellis A., Wieseler J., Favret J., Johnson K.W., Rice K.C., Maier S.F., Falci S., Watkins L.R.: Systemic administration of propentofylline, ibudilast, and (+)‑naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain. J. Pain, 2014; 15: 407‑421
  Google Scholar
• 19. Feng J., Misu T., Fujihara K., Sakoda S., Nakatsuji Y., Fukaura H., Kikuchi S., Tashiro K., Suzumura A., Ishii N., Sugamura K., Nakashima I., Itoyama Y.: Ibudilast, a nonselective phosphodiesterase inhibitor, regulates TH1/TH2 balance and NKT cell subset in multiple sclerosis. Mult. Scler., 2004; 10: 494‑498
  Google Scholar
• 20. Fujimoto T., Sakoda S., Fujimura H., Yanagihara T.: Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J. Neuroimmunol., 1999; 95: 35‑42
  Google Scholar
• 21. Fujishige K., Kotera J., Omori K.: Striatum – and testis‑specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur. J. Biochem., 1999; 266, 1118‑1127
  Google Scholar
• 22. Fukuyama H., Kimura J., Yamaguchi S., Yamauchi H., Ogawa M., Doi T., Yonekura Y., Konishi J.: Pharmacological effects of ibudilast on cerebral circulation: a PET study. Neurol. Res., 1993; 15: 169‑173
  Google Scholar
• 23. Giampa C., Laurenti D., Anzilotti S., Bernardi G., Menniti F.S., Fusco F.R.: Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One, 2010; 5: 13417
  Google Scholar
• 24. Gibson L.C., Hastings S.F., McPhee I., Clayton r.A., Darroch C.E., Mackenzie A., Mackenzie F.L., Nagasawa M., Stevens P.A., Macken‑ zie S.J.: The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur. J. Pharmacol., 2006; 538: 39‑42
  Google Scholar
• 25. Hameed H., Hameed M., Christo P.J.: The effect of morphine on glial cells as a potential therapeutic target for pharmacological development of analgesic drugs. Curr. Pain Headache Rep., 2010; 14: 96‑104
  Google Scholar
• 26. Houslay M.D., Schafer P., Zhang K.Y.: Phosphodiesterase‑4 as a therapeutic target. Drug Discov. Today, 2005; 10: 1503‑1519
  Google Scholar
• 27. Huang Z., Liu S., Zhang L., Salem M., Greig G.M., Chan C.C., Nat‑ sumeda Y., Noguchi K.: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci., 2006; 78: 2663‑2668
  Google Scholar
• 28. Hutchinson M.R., Lewis S.S., Coats B.D., Skyba D.A., Crysdale N.Y., Berkelhammer D.L., Brzeski A., Northcutt A., Vietz C.M., Judd C.M., Maier S.F., Watkins L.R., Johnson K.W.: Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav. Immun., 2009; 23: 240‑250
  Google Scholar
• 29. Hutchinson M.R., Zhang Y., Shridhar M., Evans J.H., Buchanan M.M., Zhao T.X., Slivka P.F., Coats B.D., Rezvani N., Wieseler J., Hughes T.S., Landgraf K.E, Chan S., Fong S., Phipps S. i wsp.: Evidence that opioids may have toll‑like receptor 4 and MD‑2 effects. Brain Behav. Immun., 2010; 24: 83‑95
  Google Scholar
• 30. Ibudilast in the Treatment of Medication Overuse Headache: A Double‑blind, Randomised, Placebo‑controlled Pilot Study. www. ClinicalTrials.gov. Identifier: NCT01317992 (07.09.2014)
  Google Scholar
• 31. Inoue N., Fukuda S., Inada T., Sameshima E., Tokushima Y., Harada M.: Effect of ibudilast on the reciprocal inhibitory visual‑vestibular interaction closely related to dizziness after cerebral ischemia. J. Stroke Cerebrovasc. Dis. 2014; 23: 51‑55
  Google Scholar
• 32. Inoue N., Harada M.: Effect of ibudilast on non‑specific symptoms in patients with chronic cerebral ischemia. Analysis of cerebral blood flow. Arzneimittelforschung, 2008; 58: 277‑282
  Google Scholar
• 33. Johnson J.L., Kwok Y.H., Sumracki N.M., Swift J.E., Hutchinson M.R., Johnson K., Williams D.B., Tuke J., Rolan P.E.: Glial attenuation with ibudilast in the treatment of medication overuse headache: a double‑blind, randomized, placebo‑controlled pilot trial of efficacy and safety. Headache, 2015; 55: 1192‑1208
  Google Scholar
• 34. Kagitani‑Shimono K., Mohri I., Fujitani Y., Suzuki K., Ozono K., Urade Y., Taniike M.: Anti‑inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model. J. Neuroinflammation, 2005; 2: 10
  Google Scholar
• 35. Kehler J., Kilburn J.P.: Patented PDE10A inhibitors: novel compounds since 2007. Expert Opin. Ther. Pat., 2009; 19: 1715‑1725
  Google Scholar
• 36. Kelly M.P., Logue S.F., Brennan J., Day J.P., Lakkaraju S., Jiang L., Zhong X., Tam M., Sukoff Rizzo S.J., Platt B.J., Dwyer J.M., Neal S., Pulito V.L., Agostino M.J., Grauer S.M. i wsp.: Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease‑related phenotypes. Proc. Natl. Acad. Sci. USA, 2010; 107: 8457‑8462
  Google Scholar
• 37. Kishi Y., Ohta S., Kasuya N., Tatsumi M., Sawada M., Sakita S., Ashikaga T., Numano F.: Ibudilast modulates platelet‑endothelium interaction mainly through cyclic GMP‑dependent mechanism. J. Cardiovasc. Pharmacol., 2000; 36: 65‑70
  Google Scholar
• 38. Ledeboer A., Hutchinson M.R., Watkins L.R., Johnson K.W.: Ibudilast (AV‑411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin. Investig. Drugs, 2007; 16: 935‑950
  Google Scholar
• 39. Ledeboer A., Liu T., Shumilla J.A., Mahoney J.H., Vijay S., Gross M.I., Vargas J.A., Sultzbaugh L., Claypool M.D., Sanftner L.M., Watkins L.R., Johnson K.W.: The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol., 2006; 2: 279‑291
  Google Scholar
• 40. Lee J.Y., Cho E., Ko Y.E., Kim I., Lee K.J., Kwon S.U., Kang D.W., Kim J.S.: Ibudilast, a phosphodiesterase inhibitor with anti‑inflammatory activity, protects against ischemic brain injury in rats. Brain Res., 2012; 1431: 97‑106
  Google Scholar
• 41. Lilius T.O., Rauhala P.V., Kambur O., Kalso E.A.: Modulation of morphine‑induced antinociception in acute and chronic opioid treatment by ibudilast. Anesthesiology, 2009; 111: 1356‑1364
  Google Scholar
• 42. Lolis E.: Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Curr. Opin. Pharmacol., 2001; 1: 662‑668
  Google Scholar
• 43. Loughney K., Snyder P.B., Uher L., Rosman G.J., Ferguson K., Florio V.A.: Isolation and characterization of PDE10A, a novel human 3’, 5’‑cyclic nucleotide phosphodiesterase. Gene, 1999; 234: 109‑117
  Google Scholar
• 44. Maurice H.D., Ke H., Ahmad F., Wang Y., Chung J., Manganiello V.C.: Advances in targeting cyclic nucleotide phosphodiesterases. Nat. Rev. Drug Discov., 2014; 13: 290‑314
  Google Scholar
• 45. Mizuno T., Kurotani T., Komatsu Y., Kawanokuchi J., Kato H., Mitsuma N., Suzumura A.: Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology, 2004; 46: 404‑411
  Google Scholar
• 46. Mo M., Erdelyi I., Szigeti‑Buck K., Benbow J.H., Ehrlich B.E.: Prevention of paclitaxel‑induced peripheral neuropathy by lithium pretreatment. FASEB J., 2012; 26: 4696‑4709
  Google Scholar
• 47. Nitu A.N., Wallihan r., Skljarevski V., Ramadan N.M.: Emerging trends in the pharmacotherapy of chronic pain. Expert Opin. Investig. Drugs, 2003; 12: 545‑559
  Google Scholar
• 48. Ohashi M., Ohkubo H., Kito J., Nishino K.: A new vasodilator 3‑isobutyryl‑2‑isopropylpyrazolo[1,5‑a] pyridine (KC‑404) has a dual mechanizm of action on platelet aggregation. Arch. Int. Pharmacodyn. Ther., 1986; 283: 321‑334
  Google Scholar
• 49. Ohtomo H.: Effect of ibudilast (Ketas) in preventing the recurrence of cerebral infarction. Yakuri to Rinsho (Jpn. Pharmacol. Ther.), 1995; 23: 139‑157
  Google Scholar
• 50. Phase I Safety Interaction Trial of Ibudilast With Methamphetamine. www.ClinicalTrials.gov. Identifier: NCT01217970 (27.08.2014)
  Google Scholar
• 51. Phase IIa Study of AV411, a Glial Activation Inhibitor, for Opioid Withdrawal. www.ClinicalTrials.gov. Identifier: NCT00723177 (11.11.2016)
  Google Scholar
• 52. Poulsen J.N., Larsen F., Duroux M., Gazerani P.: Primary culture of trigeminal satellite glial cells: a cell‑based platform to study morphology and function of peripheral glia. Int. J. Physiol. Pathophysiol. Pharmacol., 2014; 6: 1‑12
  Google Scholar
• 53. Ramirez A.D., Smith S.M.: Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. Cent. Nerv. Syst. Agents Med. Chem., 2014; 14: 72‑82
  Google Scholar
• 54. Rile G., Yatomi Y., Qi r., Satoh K., Ozaki Y.: Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells. Thromb. Res., 2001; 102: 239‑246
  Google Scholar
• 55. Rodgers K.M., Bercum F.M., McCallum D.L., Rudy J.W., Frey L.C., Johnson K.W., Watkins L.R., Barth D.S.: Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury. J. Neurotrauma, 2012; 29: 1886‑1897
  Google Scholar
• 56. Roger T., David J., Glauser M.P., Calandra T.: MIF regulates innate immune responses through modulation of Toll‑like receptor 4. Nature, 2001; 414: 920‑924
  Google Scholar
• 57. Rolan P., Gibbons J.A., He L., Chang E., Jones D., Gross M.I., Davidson J.B., Sanftner L.M., Johnson K.W.: Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses. Br. J. Clin. Pharmacol., 2008; 66: 792‑801
  Google Scholar
• 58. Rolan P., Hutchinson M., Johnson K.: Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert Opin. Pharmacother., 2009; 10: 2897‑2904
  Google Scholar
• 59. Sanftner L.M., Gibbons J.A., Gross M.I., Suzuki B.M., Gaeta F.C., Johnson K.W.: Cross‑species comparisons of the pharmacokinetics of ibudilast. Xenobiotica, 2009; 39: 964‑977
  Google Scholar
• 60. Schmidt C.J., Chapin D.S., Cianfrogna J., Corman M.L., Hajos M., Harms J.F., Hoffman W.E., Lebel L.A., McCarthy S.A., Nelson F.R., Proulx‑LaFrance C., Majchrzak M.J., Ramirez A.D., Schmidt K., Seymour P.A. i wsp.: Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J. Pharmacol. Exp. Ther., 2008; 325: 681‑690
  Google Scholar
• 61. Schwarz J.M., Hutchinson M.R., Bilbo S.D.: Early‑life experience decreases drug‑induced reinstatement of morphine CPP in adulthood via microglial‑specific epigenetic programming of anti‑inflammatory IL‑10 expression. J. Neurosci., 2011; 31: 17835‑17847
  Google Scholar
• 62. Schwarz J.M., Smith S.H., Bilbo S.D.: FACS analysis of neuronal‑glial interactions in the nucleus accumbens following morphine administration. Psychopharmacology, 2013; 230: 525‑535
  Google Scholar
• 63. Shah A., Silverstein P.S., Singh D.P., Kumar A.: Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF‑κB pathway in methamphetamine‑mediated increase in IL‑6 and IL‑8 expression in astrocytes. J. Neuroinflammation, 2012; 9: 52
  Google Scholar
• 64. Shi X., Leng L., Wang T., Wang W., Du X., Li J., McDonald C., Chen Z., Murphy J.W., Lolis E., Noble P., Knudson W., Bucala r.: CD44 is the signaling component of the macrophage migration inhibitory factor‑CD74 receptor complex. Immunity, 2006; 25: 595‑606
  Google Scholar
• 65. Shinohara Y., Kusunoki T., Nakashima M.: Clinical efficacy of ibudilast on vertigo and dizziness observed in patients with cerebral infarction in the chronic stage – a double‑blind, randomized, placebo‑controlled trial with a run‑in period. Neurol. Ther., 2002; 19: 177‑187
  Google Scholar
• 66. Siuciak J.A., Chapin D.S., Harms J.F., Lebel L.A., McCarthy S.A., Chambers L., Shrikhande A., Wong S., Menniti F.S., Schmidt C.J.: Inhibition of the striatum‑enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology, 2006; 51: 386‑396
  Google Scholar
• 67. Snider S.E., Hendrick E.S., Beardsley P.M.: Glial cell modulators attenuate methamphetamine self‑administration in the rat. Eur. J. Pharmacol., 2013; 701: 124‑130
  Google Scholar
• 68. Snider S.E., Vunck S.A., van den Oord E.J., Adkins D.E., McClay J.L., Beardsley P.M.: The glial cell modulators, ibudilast and its amino analog, AV1013, attenuate methamphetamine locomotor activity and its sensitization in mice. Eur. J. Pharmacol., 2012; 679: 75‑80
  Google Scholar
• 69. Soderling S.H., Bayuga S.J., Beavo J.A.: Isolation and characterization of a dual‑substrate phosphodiesterase gene family: PDE10A. Proc. Natl. Acad. Sci. USA, 1999; 96, 7071‑7076
  Google Scholar
• 70. Sone H., Okuda Y., Asakura Y., Asano M., Mizutani M., Bannai C., Yamashita K.: Efficacy of Ibudilast on lower limb circulation of diabetic patients with minimally impaired baseline flow: a study using color Doppler ultrasonography and laser Doppler flowmetry. Angiology, 1995; 46: 699‑703
  Google Scholar
• 71. Souness J.E., Villamil M.E., Scott L.C., Tomkinson A., Giembycz M.A., Raeburn D.: Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone. Br. J. Pharmacol., 1994; 111: 1081‑1088
  Google Scholar
• 72. Suzumura A., Ito A., Mizuno T.: Phosphodiesterase inhibitors suppress IL‑12 production with microglia and T helper 1 development. Mult. Scler., 2003; 9: 574‑578
  Google Scholar
• 73. Suzumura A., Ito A., Yoshikawa M., Sawada M.: Ibudilast suppresses TNFα production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res., 1999; 837: 203‑212
  Google Scholar
• 74. Takahashi M., Terwilliger r., Lane C., Mezes P.S., Conti M., Duman r.S.: Chronic antidepressant administration increases the expression of cAMP‑specific phosphodiesterase 4A and 4B isoforms. J. Neurosci., 1999; 19: 610‑618
  Google Scholar
• 75. Takuma K., Lee E., Enomoto r., Mori K., Baba A., Matsuda T.: Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. Br. J. Pharmacol., 2001; 133: 841‑848
  Google Scholar
• 76. Targeting Glial Inhibition to Attenuate Chronic Migraine: An international double – blind, randomized, placebo‑controlled trial of ibudilast. www.ClinicalTrials.gov. Identifier: NCT01389193 (28.12.2015)
  Google Scholar
• 77. Threlfell S., Sammut S., Menniti F.S., Schmidt C.J., West A.R.: Inhibition of phosphodiesterase 10A increases the responsiveness of striatal projection neurons to cortical stimulation. J. Pharmacol. Exp. Ther., 2009; 328: 785‑795
  Google Scholar
• 78. Tominaga Y., Nakamura Y., Tsuji K., Shibata T., Kataoka K.: Ibudilast protects against neuronal damage induced by glutamate in cultured hippocampal neurons. Clin. Exp. Pharmacol. Physiol., 1996; 23: 519‑523
  Google Scholar
• 79. Tu Z., Fan J., Li S., Jones L.A., Cui J., Padakanti P.K., Xu J., Zeng D., Shoghi K.I., Perlmutter J.S., Mach r.H.: Radiosynthesis and in vivo evaluation of [11C]MP‑10 as a PET probe for imaging PDE10A in rodent and non‑human primate brain. Bioorg. Med. Chem., 2011; 19: 1666‑1673
  Google Scholar
• 80. Verhoest P.R., Chapin D.S., Corman M., Fonseca K., Harms J.F., Hou X., Marr E.S., Menniti F.S., Nelson F., O’Connor r., Pandit J., Proulx‑Lafrance C., Schmidt A.W., Schmidt C.J., Suiciak J.A., Liras S.: Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2‑[4‑(1‑methyl‑4‑pyridin‑4‑yl‑1H‑pyr‑ azol‑3‑yl)‑phenoxymethyl]‑quinoline (PF‑2545920) for the treatment of schizophrenia. J. Med. Chem., 2009; 52: 7946‑7949
  Google Scholar
• 81. Vitolo O.V., Sant’Angelo A., Costanzo V., Battaglia F., Arancio O., Shelanski M.: Amyloid beta‑peptide inhibition of the PKA/ CREB pathway and long‑term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. USA, 2002; 99: 13217‑13221
  Google Scholar
• 82. Wakita H., Tomimoto H., Akiguchi I., Lin J.X., Ihara M., Ohtani r., Shibata M.: Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Res., 2003; 992: 53‑59
  Google Scholar
• 83. Wang H., Mei Z.I., Zhong K.L., Hu M., Long Y., Miao M.X., Li N., Yan T.H., Hong H.: Pretreatment with antiasthmatic drug ibudilast ameliorates Aβ1‑42‑induced memory impairment and neurotoxicity in mice. Pharmacol. Biochem. Behav., 2014; 124: 373‑379
  Google Scholar
• 84. Watkins L.R., Hutchinson M.R., Johnston I.N., Maier S.F.: Glia: novel counter‑regulators of opioid analgesia. Trends Neurosci., 2005; 28: 661‑669
  Google Scholar
• 85. Watkins L.R., Hutchinson M.R., Ledeboer A., Wieseler‑Frank J., Milligan E.D., Maier S.F.: Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav. Immunol., 2007; 21: 131‑146
  Google Scholar
• 86. Wayman C., Phillips S., Lunny C., Webb T., Fawcett L., Baxendale r., Burgess G.: Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int. J. Impot. Res., 2005; 17: 216‑223
  Google Scholar
• 87. Weber C., Kraemer S., Drechsler M., Lue H., Koenen r.R., Kapurniotu A., Zernecke A., Bernhagen J.: Structural determinants of MIF functions in CXCR2‑mediated inflammatory and atherogenic leukocyte recruitment. Proc. Natl. Acad. Sci. USA, 2008; 105: 16278‑16283
  Google Scholar
• 88. Yang L., Calingasan N.Y., Lorenzo B.J., Beal M.F.: Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. Exp. Neurol., 2008; 211: 311‑314
  Google Scholar
• 89. Yoshikawa M., Suzumura A., Ito A., Tamaru T., Takayanagi T.: Effect of phosphodiesterase inhibitors on nitric oxide production by glial cells. Tohoku J. Exp. Med., 2002; 196: 167‑177
  Google Scholar
• 90. Yoshioka A., Shimizu Y., Hirose G., Kitasato H., Pleasure D.: Cyclic AMP‑elevating agents prevent oligodendroglial excitotoxicity. J. Neurochem., 1998; 70: 2416‑2423
  Google Scholar
• 91. Yoshioka M., Suda N., Mori K., Ueno K., Itoh Y., Togashi H., Matsumoto M.: Effects of ibudilast on hippocampal long‑term potentiation and passive avoidance responses in rats with transient cerebral ischemia. Pharmacol. Res., 2002; 45: 305‑311
  Google Scholar
• 92. Zhaleh M., Panahi M., Ghafurian Broujerdnia M., Ghorbani r., Ahmadi Angali K., Saki G.: Role of phosphodiesterase inhibitor Ibudilast in morphine‑induced hippocampal injury. J. Inj. Violence Res., 2014; 6: 72‑78
  Google Scholar
• 93. Zhang H.T., Huang Y., Jin S.L., Frith S.A., Suvarna N., Conti M., O’Donnell J.M.: Antidepressant‑like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology, 2002; 27: 587‑595
  Google Scholar

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