Pharmacological Modulation of Glutamatergic and Neuroinflammatory Pathways in a Lafora Disease Mouse Model.
Adolescent
Animals
Disease Models, Animal
Dual-Specificity Phosphatases
/ metabolism
Humans
Lafora Disease
/ genetics
Memantine
Mice
Mice, Knockout
Minocycline
/ pharmacology
Myoclonic Epilepsies, Progressive
Protein Tyrosine Phosphatases, Non-Receptor
/ genetics
Resveratrol
Ubiquitin-Protein Ligases
/ metabolism
Cognitive impairment
Lafora disease
Memantine
Minocycline
Neuroinflammation
Resveratrol
Riluzole
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Oct 2022
Oct 2022
Historique:
received:
11
02
2022
accepted:
04
07
2022
pubmed:
15
7
2022
medline:
14
9
2022
entrez:
14
7
2022
Statut:
ppublish
Résumé
Lafora disease (LD) is a fatal rare neurodegenerative disorder that affects young adolescents and has no treatment yet. The hallmark of LD is the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), in the brain and peripheral tissues. LD is caused by mutations in either EPM2A or EPM2B genes, which, respectively, encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, with identical clinical features. LD knockout mouse models (Epm2a - / - and Epm2b - / -) recapitulate PG body accumulation, as in the human pathology, and display alterations in glutamatergic transmission and neuroinflammatory pathways in the brain. In this work, we show the results of four pre-clinical trials based on the modulation of glutamatergic transmission (riluzole and memantine) and anti-neuroinflammatory interventions (resveratrol and minocycline) as therapeutical strategies in an Epm2b - / - mouse model. Drugs were administered in mice from 3 to 5 months of age, corresponding to early stage of the disease, and we evaluated the beneficial effect of the drugs by in vivo behavioral phenotyping and ex vivo histopathological brain analyses. The behavioral assessment was based on a battery of anxiety, cognitive, and neurodegenerative tests and the histopathological analyses included a panel of markers regarding PG accumulation, astrogliosis, and microgliosis. Overall, the outcome of ameliorating the excessive glutamatergic neurotransmission present in Epm2b - / - mice by memantine displayed therapeutic effectiveness at the behavioral levels. Modulation of neuroinflammation by resveratrol and minocycline also showed beneficial effects at the behavioral level. Therefore, our study suggests that both therapeutical strategies could be beneficial for the treatment of LD patients. A mouse model of Lafora disease (Epm2b-/-) was used to check the putative beneficial effect of different drugs aimed to ameliorate the alterations in glutamatergic transmission and/or neuroinflammation present in the model. Drugs in blue gave a more positive outcome than the rest.
Identifiants
pubmed: 35835895
doi: 10.1007/s12035-022-02956-7
pii: 10.1007/s12035-022-02956-7
pmc: PMC9463199
doi:
Substances chimiques
Ubiquitin-Protein Ligases
EC 2.3.2.27
Dual-Specificity Phosphatases
EC 3.1.3.48
Protein Tyrosine Phosphatases, Non-Receptor
EC 3.1.3.48
Minocycline
FYY3R43WGO
Resveratrol
Q369O8926L
Memantine
W8O17SJF3T
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6018-6032Subventions
Organisme : NINDS NIH HHS
ID : P01 NS097197
Pays : United States
Organisme : Ministerio de Ciencia, Innovación y Universidades
ID : PID2020-112972RB-I00
Organisme : Instituto de Salud Carlos III
ID : ACCI2020
Informations de copyright
© 2022. The Author(s).
Références
Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, Minassian BA (2016) Lafora disease. Epileptic Disord 18(S2):38–62
pubmed: 27702709
pmcid: 5777303
Lafora GR, Glueck B (1911) Beitrag zur histogpathologie der myoklonischen epilepsie. Gesamte Neurol Psychiatr 6:1–14
Sakai M, Austin J, Witmer F, Trueb L (1970) Studies in myoclonus epilepsy (Lafora body form). II. Polyglucosans in the systemic deposits of myoclonus epilepsy and in corpora amylacea. Neurology 20(2):160–176
pubmed: 4188951
Mitra S, Gumusgoz E, Minassian BA (2022) Lafora disease: current biology and therapeutic approaches. Rev Neurol (Paris) 178:315–325
Markussen KH, Macedo JKA, Machio M, Dolce A, Goldberg YP, Vander Kooi CW, Gentry MS (2021) The 6th International Lafora Epilepsy Workshop: advances in the search for a cure. Epilepsy Behav 119:107975
pubmed: 33946009
pmcid: 8154720
Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R et al (1998) Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20(2):171–174
pubmed: 9771710
Serratosa JM, Gomez-Garre P, Gallardo ME, Anta B, de Bernabe DB, Lindhout D, Augustijn PB, Tassinari CA et al (1999) A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet 8(2):345–352
pubmed: 9931343
Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC, Avanzini G, Elia M et al (2003) Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet 35(2):125–127
pubmed: 12958597
Garcia-Gimeno MA, Knecht E, Sanz P (2018) Lafora disease: a ubiquitination-related pathology. Cells 7(8):8
Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA (2018) Lafora disease - from pathogenesis to treatment strategies. Nat Rev Neurol 14(10):606–617
pubmed: 30143794
pmcid: 6317072
Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H et al (2002) Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet 11(11):1251–1262
pubmed: 12019206
DePaoli-Roach AA, Tagliabracci VS, Segvich DM, Meyer CM, Irimia JM, Roach PJ (2010) Genetic depletion of the malin E3 ubiquitin ligase in mice leads to lafora bodies and the accumulation of insoluble laforin. J Biol Chem 285(33):25372–25381
pubmed: 20538597
pmcid: 2919100
Turnbull J, Wang P, Girard JM, Ruggieri A, Wang TJ, Draginov AG, Kameka AP, Pencea N et al (2010) Glycogen hyperphosphorylation underlies lafora body formation. Ann Neurol 68(6):925–933
pubmed: 21077101
Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millan B, Heredia M et al (2012) Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet 21(7):1521–1533
pubmed: 22186026
Garcia-Cabrero AM, Marinas A, Guerrero R, de Cordoba SR, Serratosa JM, Sanchez MP (2012) Laforin and malin deletions in mice produce similar neurologic impairments. J Neuropathol Exp Neurol 71(5):413–421
pubmed: 22487859
Valles-Ortega J, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Canas X et al (2011) Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Mol Med 3(11):667–681
pubmed: 21882344
pmcid: 3377110
Taneja K, Ganesh S (2021) Dendritic spine abnormalities correlate with behavioral and cognitive deficits in mouse models of Lafora disease. J Comp Neurol 529(6):1099–1120
pubmed: 32785985
Ortolano S, Vieitez I, Agis-Balboa RC, Spuch C (2014) Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease. Mol Brain 7:7
pubmed: 24472629
pmcid: 3917365
Rubio-Villena C, Viana R, Bonet J, Garcia-Gimeno MA, Casado M, Heredia M, Sanz P (2018) Astrocytes: new players in progressive myoclonus epilepsy of Lafora type. Hum Mol Genet 27(7):1290–1300
pubmed: 29408991
pmcid: 6059194
Auge E, Pelegri C, Manich G, Cabezon I, Guinovart JJ, Duran J, Vilaplana J (2018) Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease. Glia 66(10):2094–2107
pubmed: 30152044
pmcid: 6240358
Lopez-Gonzalez I, Viana R, Sanz P, Ferrer I (2017) Inflammation in Lafora disease: evolution with disease progression in laforin and Malin knock-out mouse models. Mol Neurobiol 54(5):3119–3130
pubmed: 27041370
Lahuerta M, Gonzalez D, Aguado C, Fathinajafabadi A, Garcia-Gimenez JL, Moreno-Estelles M, Roma-Mateo C, Knecht E et al (2020) Reactive glia-derived neuroinflammation: a novel hallmark in Lafora progressive myoclonus epilepsy that progresses with age. Mol Neurobiol 57(3):1607–1621
pubmed: 31808062
Munoz-Ballester C, Berthier A, Viana R, Sanz P (2016) Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease. Biochim Biophys Acta 6:1074–1083
Munoz-Ballester C, Santana N, Perez-Jimenez E, Viana R, Artigas F, Sanz P (2019) In vivo glutamate clearance defects in a mouse model of Lafora disease. Exp Neurol 320:112959
pubmed: 31108086
pmcid: 6708466
Perez-Jimenez E, Viana R, Munoz-Ballester C, Vendrell-Tornero C, Moll-Diaz R, Garcia-Gimeno MA, Sanz P (2021) Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: implications in Lafora disease. Glia 69(5):1170–1183
pubmed: 33368637
Garcia-Cabrero AM, Sanchez-Elexpuru G, Serratosa JM, Sanchez MP (2014) Enhanced sensitivity of laforin- and malin-deficient mice to the convulsant agent pentylenetetrazole. Front Neurosci 8:291
pubmed: 25309313
pmcid: 4162417
Duran J, Gruart A, Garcia-Rocha M, Delgado-Garcia JM, Guinovart JJ (2014) Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet 23(12):3147–3156
pubmed: 24452334
Berthier A, Paya M, Garcia-Cabrero AM, Ballester MI, Heredia M, Serratosa JM, Sanchez MP, Sanz P (2016) Pharmacological interventions to ameliorate neuropathological symptoms in a mouse model of Lafora disease. Mol Neurobiol 53(2):1296–1309
pubmed: 25627694
Molla B, Heredia M, Sanz P (2021) Modulators of neuroinflammation have a beneficial effect in a Lafora disease mouse model. Mol Neurobiol 58(6):2508–2522
pubmed: 33447969
pmcid: 8167455
Bissaro M, Moro S (2019) Rethinking to riluzole mechanism of action: the molecular link among protein kinase CK1delta activity, TDP-43 phosphorylation, and amyotrophic lateral sclerosis pharmacological treatment. Neural Regen Res 14(12):2083–2085
pubmed: 31397342
pmcid: 6788255
Kennel P, Revah F, Bohme GA, Bejuit R, Gallix P, Stutzmann JM, Imperato A, Pratt J (2000) Riluzole prolongs survival and delays muscle strength deterioration in mice with progressive motor neuronopathy (pmn). J Neurol Sci 180(1–2):55–61
pubmed: 11090865
Hunsberger HC, Weitzner DS, Rudy CC, Hickman JE, Libell EM, Speer RR, Gerhardt GA, Reed MN (2015) Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression. J Neurochem 135(2):381–394
pubmed: 26146790
pmcid: 4717473
Hascup KN, Findley CA, Britz J, Esperant-Hilaire N, Broderick SO, Delfino K, Tischkau S, Bartke A et al (2021) Riluzole attenuates glutamatergic tone and cognitive decline in AbetaPP/PS1 mice. J Neurochem 156(4):513–523
pubmed: 33107040
Rogawski MA, Wenk GL (2003) The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 9(3):275–308
pubmed: 14530799
pmcid: 6741669
Wenk GL, Parsons CG, Danysz W (2006) Potential role of N-methyl-D-aspartate receptors as executors of neurodegeneration resulting from diverse insults: focus on memantine. Behav Pharmacol 17(5–6):411–424
pubmed: 16940762
Repossi G, Das UN, Eynard AR (2020) Molecular basis of the beneficial actions of resveratrol. Arch Med Res 51(2):105–114
pubmed: 32111491
Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J (2021) Anti-inflammatory action and mechanisms of resveratrol. Molecules 26(1):molecules26010229
Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, Marambaud P (2012) Resveratrol mitigates lipopolysaccharide- and Abeta-mediated microglial inflammation by inhibiting the TLR4/NF-kappaB/STAT signaling cascade. J Neurochem 120(3):461–472
pubmed: 22118570
Venigalla M, Sonego S, Gyengesi E, Sharman MJ, Munch G (2016) Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer’s disease. Neurochem Int 95:63–74
pubmed: 26529297
Garrido-Mesa N, Zarzuelo A, Galvez J (2013) Minocycline: far beyond an antibiotic. Br J Pharmacol 169(2):337–352
pubmed: 23441623
pmcid: 3651660
Moller T, Bard F, Bhattacharya A, Biber K, Campbell B, Dale E, Eder C, Gan L et al (2016) Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64(10):1788–1794
pubmed: 27246804
Li J, Sung M, Rutkove SB (2013) Electrophysiologic biomarkers for assessing disease progression and the effect of riluzole in SOD1 G93A ALS mice. PLoS ONE 8(6):e65976
pubmed: 23762454
pmcid: 3675066
Schmidt J, Schmidt T, Golla M, Lehmann L, Weber JJ, Hubener-Schmid J, Riess O (2016) In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem 138(1):150–162
pubmed: 26990650
Canistro D, Bonamassa B, Pozzetti L, Sapone A, Abdel-Rahman SZ, Biagi GL, Paolini M (2009) Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice. Food Chem Toxicol 47(2):454–461
pubmed: 19101601
Singleton RH, Yan HQ, Fellows-Mayle W, Dixon CE (2010) Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J Neurotrauma 27(6):1091–1099
pubmed: 20560755
pmcid: 2943501
Molinaro G, Battaglia G, Riozzi B, Di Menna L, Rampello L, Bruno V, Nicoletti F (2009) Memantine treatment reduces the expression of the K(+)/Cl(-) cotransporter KCC2 in the hippocampus and cerebral cortex, and attenuates behavioural responses mediated by GABA(A) receptor activation in mice. Brain Res 1265:75–79
pubmed: 19236854
Ahmadirad N, Shojaei A, Javan M, Pourgholami MH, Mirnajafi-Zadeh J (2014) Effect of minocycline on pentylenetetrazol-induced chemical kindled seizures in mice. Neurol Sci 35(4):571–576
pubmed: 24122023
Lalonde R, Strazielle C (2011) Brain regions and genes affecting limb-clasping responses. Brain Res Rev 67(1–2):252–259
pubmed: 21356243
Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, Garden GA (2010) A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp (39). https://doi.org/10.3791/1787
Seibenhener ML, Wooten MC (2015) Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 96:e52434
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328
pubmed: 17406592
pmcid: 3623971
Abdel Rasheed NO, El Sayed NS, El-Khatib AS (2018) Targeting central beta2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice. Prog Neuropsychopharmacol Biol Psychiatry 86:65–75
pubmed: 29782959
El Sayed NS, Ghoneum MH (2020) Antia, a natural antioxidant product, attenuates cognitive dysfunction in streptozotocin-induced mouse model of sporadic alzheimer’s disease by targeting the amyloidogenic, inflammatory, autophagy, and oxidative stress pathways. Oxid Med Cell Longev 2020:4386562
pubmed: 32655767
pmcid: 7320293
RStudio_Team (2020) RStudio: Integrated development for R. RStudio, PBC, Boston, MA. https://www.rstudio.com/
Cohen J (1988) Statistical power analysis for the behavioral sciences (2nd edition). Routledge, New York. https://doi.org/10.4324/9780203771587
Kraemer HC, Morgan GA, Leech NL, Gliner JA, Vaske JJ, Harmon RJ (2003) Measures of clinical significance. J Am Acad Child Adolesc Psychiatry 42(12):1524–1529
pubmed: 14627890
Felsky D, Roostaei T, Nho K, Risacher SL, Bradshaw EM, Petyuk V, Schneider JA, Saykin A et al (2019) Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat Commun 10(1):409
pubmed: 30679421
pmcid: 6345810
Ahonen S, Nitschke S, Grossman TR, Kordasiewicz H, Wang P, Zhao X, Guisso DR, Kasiri S et al (2021) Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease. Brain 144(10):2985–2993
pubmed: 33993268
pmcid: 8634080
Tang B, Frasinyuk MS, Chikwana VM, Mahalingan KK, Morgan CA, Segvich DM, Bondarenko SP, Mrug GP et al (2020) Discovery and development of small-molecule inhibitors of glycogen synthase. J Med Chem 63(7):3538–3551
pubmed: 32134266
pmcid: 7233370
Brewer MK, Uittenbogaard A, Austin GL, Segvich DM, DePaoli-Roach A, Roach PJ, McCarthy JJ, Simmons ZR et al (2019) Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion. Cell Metab 30(4):689-705 e686
pubmed: 31353261
pmcid: 6774808
Austin GL, Simmons ZR, Klier JE, Rondon A, Hodges BL, Shaffer R, Aziz NM, McKnight TR et al (2019) Central nervous system delivery and biodistribution analysis of an antibody-enzyme fusion for the treatment of Lafora disease. Mol Pharm 16(9):3791–3801
pubmed: 31329461
pmcid: 7189208
Israelian L, Wang P, Gabrielian S, Zhao X, Minassian BA (2020) Ketogenic diet reduces Lafora bodies in murine Lafora disease. Neurol Genet 6(6):e533
pubmed: 33324758
pmcid: 7713716
Mohammadzadeh S, Ahangari TK, Yousefi F (2019) The effect of memantine in adult patients with attention deficit hyperactivity disorder. Hum Psychopharmacol 34(1):e2687
pubmed: 30663824
Dirani M, Nasreddine W, Abdulla F, Beydoun A (2014) Seizure control and improvement of neurological dysfunction in Lafora disease with perampanel. Epilepsy Behav Case Rep 2:164–166
pubmed: 25667898
pmcid: 4307869
Goldsmith D, Minassian BA (2016) Efficacy and tolerability of perampanel in ten patients with Lafora disease. Epilepsy Behav 62:132–135
pubmed: 27459034
pmcid: 5691360
Dasgupta B, Milbrandt J (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A 104(17):7217–7222
pubmed: 17438283
pmcid: 1855377
Porro C, Cianciulli A, Calvello R, Panaro MA (2015) Reviewing the role of resveratrol as a natural modulator of microglial activities. Curr Pharm Des 21(36):5277–5291
pubmed: 26416082
Gonzalez JC, Egea J, Del Carmen GM, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, Garcia AG, Jordan J et al (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26(9):2481–2495
pubmed: 17986028
Lu Y, Yang Y, Chen W, Du N, Du Y, Gu H, Liu Q (2021) Minocycline, but not doxycycline attenuates NMDA-induced [Ca2+]i and excitotoxicity. NeuroReport 32(1):38–43
pubmed: 33252477
Nie H, Zhang H, Weng HR (2010) Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats. Neuroscience 170(3):901–912
pubmed: 20678556