Аннотация
Инсулин контролирует не только системный гомеостаз глюкозы, но и функциональную активность мозга. При сахарном диабете 2-го типа (СД2) в мозге снижается содержание инсулина и активность инсулиновой сигнальной системы. Это приводит к нарушению энергетического обмена, включая гипометаболизм глюкозы в мозге, и к когнитивным дисфункциям. Для компенсации недостатка гормона в мозге может быть использован интраназально вводимый инсулин (ИВИ). В целях повышения эффективности ИВИ для коррекции функций мозга целесообразно его комбинированное применение с веществами, наделенными свойствами нейропротекторов, в том числе со сложными гликосфинголипидами ганглиозидами. Для доставки ганглиозидов в мозг также может быть использовано их интраназальное введение (ИВГ). Целью работы было оценить эффективность раздельных и совместных интраназальных введений инсулина и ганглиозидов для коррекции когнитивных нарушений у крыс Wistar с СД2, для чего использовали водный лабиринт Морриса (ВЛМ) и анализ в гиппокампе экспрессии белков (BDNF, GLUT-1, GLUT-3, GLUT-4, GFAP, PSD95) и активности протеинкиназ (Akt, GSK3β, ERK1/2), вовлеченных в процессы обучения и формирования долговременной памяти. ИВИ и ИВГ при введении крысам с СД2 улучшали пространственную ориентацию в ВЛМ, причем эффект совместного использования ИВИ и ИВГ был сходным с таковым при их раздельном применении. При совместном введении ИВИ и ИВГ отмечали сохранение активности эффекторных протеинкиназ (Akt и ERK1/2), в то время как при монотерапии ИВИ уровень их фосфорилирования был снижен. При комбинированной терапии также увеличивалось фосфорилирование GSK3β по Ser9, защищающее нейроны от тауропатии. Таким образом, совместное применение ИВИ и ИВГ улучшает функциональное состояние компонентов инсулиновой системы в мозге крыс с СД2, хотя значимо не усиливает эффекты ИВИ на показатели долговременной памяти.
Литература
Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 2012:384017. s://doi.org/10.1155/2012/384017
Petersen MC, Shulman G (2018) Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 98:2133–2223. s://doi.org/10.1152/physrev.00063.2017
White MF, Kahn CR (2021) Insulin action at a molecular level – 100 years of progress. Mol Metab 52:101304. s://doi.org/10.1016/j.molmet.2021.101304
Vinuesa A, Pomilio C, Gregosa A, Bentivegna M, Presa J, Bellotto M, Saravia F, Beauquis J (2021) Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer's Disease. Front Neurosci 15:653651. s://doi.org/10.3389/fnins.2021.653651
Sullivan M, Fernandez-Aranda F, Camacho-Barcia L, Harkin A, Macrì S, Mora-Maltas B, Jiménez-Murcia S, O'Leary A, Ottomana AM, Presta M, Slattery D, Scholtz S, Glennon JC (2023) Insulin and disorders of behavioural flexibility. Neurosci Biobehav Rev 150:105169. s://doi.org/10.1016/j.neubiorev.2023.105169
Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382. s://doi.org/10.1038/nm1202-798
Viswaprakash N, Vaithianathan T, Viswaprakash A, Judd R, Parameshwaran K, Suppiramaniam V (2015) Insulin treatment restores glutamate (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function in the hippocampus of diabetic rats. J Neurosci Res 93:1442–1450. s://doi.org/10.1002/jnr.23589
Zhao F, Siu JJ, Huang W, Askwith C, Cao L (2019) Insulin Modulates Excitatory Synaptic Transmission and Synaptic Plasticity in the Mouse Hippocampus. Neuroscience 411:237–254. s://doi.org/10.1016/j.neuroscience.2019.05.033
Hammoud H, Netsyk O, Tafreshiha AS, Korol SV, Jin Z, Li JP, Birnir B (2021) Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age-dependent manner, normalizes GABA-activated currents in the tg-APPSwe mouse model of Alzheimer's disease. Acta Physiol 232:e13623. s://doi.org/10.1111/apha.13623
Shypshyna M, Kolesnyk O, Fedulova S, Veselovsky N (2023) Insulin modulates the paired-pulse plasticity at glutamatergic synapses of hippocampal neurons under hypoinsulinemia. Front Cell Neurosci 17:1132325. s://doi.org/10.3389/fncel.2023.1132325
Janssen JAMJL (2021) Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int J Mol Sci 22:7797. s://doi.org/10.3390/ijms22157797
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100:4162–4167. s://doi.org/10.1073/pnas.0230450100
Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol Aging 27:190–198. s://doi.org/10.1016/j.neurobiolaging.2005.01.004
Spinelli M, Fusco S, Grassi C (2019) Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline. Front Neurosci 13:788. s://doi.org/10.3389/fnins.2019.00788
Reinke C, Buchmann N, Fink A, Tegeler C, Demuth I, Doblhammer G (2022) Diabetes duration and the risk of dementia: a cohort study based on German health claims data. Age Ageing 51:afab231. s://doi.org/10.1093/ageing/afab231
Heni M, Schöpfer P, Peter A, Sartorius T, Fritsche A, Synofzik M, Häring HU, Maetzler W, Hennige AM (2014) Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans. Acta Diabetol 51:679–681. s://doi.org/10.1007/s00592-013-0546-y
Sartorius T, Peter A, Heni M, Maetzler W, Fritsche A, Häring HU, Hennige AM (2015) The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLoS One 10:e0126804. s://doi.org/10.1371/journal.pone.0126804
Derkach K, Zakharova I, Zorina I, Bakhtyukov A, Romanova I, Bayunova L, Shpakov A (2019) The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect. PLoS One 14:e0213779. s://doi.org/10.1371/journal.pone.0213779
Jurcovicova J (2014) Glucose transport in brain - effect of inflammation. Endocr Regul 48:35–48. s://doi.org/10.4149/endo_2014_01_35
Koepsell H (2020) Glucose transporters in brain in health and disease. Pflugers Arch 472:1299–1343. s://doi.org/10.1007/s00424-020-02441-x
Hernandez-Garzón E, Fernandez AM, Perez-Alvarez A, Genis L, Bascuñana P, Fernandez de la Rosa R, Delgado M, Angel Pozo M, Moreno E, McCormick PJ, Santi A, Trueba-Saiz A, Garcia-Caceres C, Tschöp MH, Araque A, Martin ED, Torres Aleman I (2016) The insulin-like growth factor I receptor regulates glucose transport by astrocytes. Glia 64:1962–1971. s://doi.org/10.1002/glia.23035
Fernandez AM, Hernandez-Garzón E, Perez-Domper P, Perez-Alvarez A, Mederos S, Matsui T, Santi A, Trueba-Saiz A, García-Guerra L, Pose-Utrilla J, Fielitz J, Olson EN, Fernandez de la Rosa R, Garcia Garcia L, Pozo MA, Iglesias T, Araque A, Soya H, Perea G, Martin ED, Torres Aleman I (2017) Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I. Diabetes 66:64–74. s://doi.org/10.2337/db16-0861
Fernandez AM, Hernandez E, Guerrero-Gomez D, Miranda-Vizuete A, Torres Aleman I (2018) A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism. Neuropharmacology 136(Pt B):216–222. s://doi.org/10.1016/j.neuropharm.2017.08.034
Blázquez E, Hurtado-Carneiro V, LeBaut-Ayuso Y, Velázquez E, García-García L, Gómez-Oliver F, Ruiz-Albusac JM, Ávila J, Pozo MÁ (2022) Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases. Front Endocrinol (Lausanne) 13:873301. s://doi.org/10.3389/fendo.2022.873301
Sukhov IB, Shipilov VN, Chistyakova OV, Trost AM, Shpakov AO (2013) Long-term intranasal insulin administration improves spatial memory in male rats with prolonged type 1 diabetes mellitus and in healthy rats. Dokl Biol Sci. 453:349–352. s://doi.org/10.1134/S001249661306015X
Rajasekar N, Nath C, Hanif K, Shukla R (2017) Intranasal Insulin Administration Ameliorates Streptozotocin (ICV)-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Memory Impairment in Rats. Mol Neurobiol 54:6507–6522. s://doi.org/10.1007/s12035-016-0169-8
Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, Donohue MC, Brewer JB, Jenkins C, Harless K, Gessert D, Aisen PS (2020) Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 77:1099–1109. s://doi.org/10.1001/jamaneurol.2020.1840
Yang L, Zhang X, Li S, Wang H, Zhang X, Liu L, Xie A (2020) Intranasal insulin ameliorates cognitive impairment in a rat model of Parkinson's disease through Akt/GSK3β signaling pathway. Life Sci 259:118159. s://doi.org/10.1016/j.lfs.2020.118159
Mastrototaro L, Roden M (2021) Insulin resistance and insulin sensitizing agents. Metabolism 125:154892. s://doi.org/10.1016/j.metabol.2021.154892
Avrova NF, Victorov IV, Tyurin VA, Zakharova IO, Sokolova TV, Andreeva NA, Stelmaschuk EV, Tyurina YY, Gonchar VS (1998) Inhibition of glutamate-induced intensification of free radical reactions by gangliosides: possible role in their protective effect in rat cerebellar granule cells and brain synaptosomes. Neurochem Res 23:945–952. s://doi.org/10.1023/a:1021076220411
Zakharova IO, Sokolova TV, Vlasova YA, Furaev VV, Rychkova MP, Avrova NF (2014) GM1 ganglioside activates ERK1/2 and Akt downstream of Trk tyrosine kinase and protects PC12 cells against hydrogen peroxide toxicity. Neurochem Res 39:2262–2275. s://doi.org/10.1007/s11064-014-1428-6
Nikolaeva S, Bayunova L, Sokolova T, Vlasova Y, Bachteeva V, Avrova N, Parnova R (2015) GM1 and GD1a gangliosides modulate toxic and inflammatory effects of E. coli lipopolysaccharide by preventing TLR4 translocation into lipid rafts. Biochim Biophys Acta 1851:239–247. s://doi.org/10.1016/j.bbalip.2014.12.004
Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V (2020) Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front Neurosci 14:572965. s://doi.org/10.3389/fnins.2020.572965
Galleguillos D, Wang Q, Steinberg N, Zaidi A, Shrivastava G, Dhami K, Daskhan GC, Schmidt EN, Dworsky-Fried Z, Giuliani F, Churchward M, Power C, Todd K, Taylor A, Macauley MS, Sipione S (2022) Anti-inflammatory role of GM1 and other gangliosides on microglia. J Neuroinflammation 19:9. s://doi.org/10.1186/s12974-021-02374-x
Zakharova IO, Avrova NF (2001) The effect of cold stress on ganglioside fatty acid composition and ganglioside-bound sialic acid content of rat brain subcellular fractions. J Therm Biol 26:215–222. s://doi.org/10.1016/s0306-4565(00)00045-0
Vanier MT, Holm M, Ohman R, Svennerholm L (1971) Developmental profiles of gangliosides in human and rat brain. J Neurochem 18:581–592. s://doi.org/10.1111/j.1471-4159.1971.tb11988.x
Derkach KV, Bondareva VM, Chistyakova OV, Berstein LM, Shpakov AO (2015) The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes. Int J Endocrinol 2015:245459. s://doi.org/10.1155/2015/245459
Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Brüning JC (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–449. s://doi.org/10.1016/j.cmet.2007.05.004
Loh K, Zhang L, Brandon A, Wang Q, Begg D, Qi Y, Fu M, Kulkarni R, Teo J, Baldock P, Brüning JC, Cooney G, Neely GG, Herzog H (2017) Insulin controls food intake and energy balance via NPY neurons. Mol Metab 6:574–584. s://doi.org/10.1016/j.molmet.2017.03.013
Shin AC, Filatova N, Lindtner C, Chi T, Degann S, Oberlin D, Buettner C (2017) Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action. Diabetes 66:1560–1571. s://doi.org/10.2337/db16-1238
Hill JM, Lesniak MA, Pert CB, Roth J (1986) Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 17:1127–1138. s://doi.org/10.1016/0306-4522(86)90082-5
Doré S, Kar S, Rowe W, Quirion R (1997) Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats. Neuroscience 80:1033–1040. s://doi.org/10.1016/s0306-4522(97)00154-1
Izumi Y, Yamada KA, Matsukawa M, Zorumski CF (2003) Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats. Diabetologia 46:1007–1012. s://doi.org/10.1007/s00125-003-1144-2
van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM (2005) Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem 94:1158–1166. s://doi.org/10.1111/j.1471-4159.2005.03269.x
Park CR, Seeley RJ, Craft S, Woods SC (2000) Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 68:509–514. s://doi.org/10.1016/s0031-9384(99)00220-6
Babri S, Badie HG, Khamenei S, Seyedlar MO (2007) Intrahippocampal insulin improves memory in a passive-avoidance task in male wistar rats. Brain Cogn 64:86–91. s://doi.org/10.1016/j.bandc.2007.01.002
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93:546–553. s://doi.org/10.1016/j.nlm.2010.02.002
Erichsen JM, Calva CB, Reagan LP, Fadel JR (2021) Intranasal insulin and orexins to treat age-related cognitive decline. Physiol Behav 234:113370. s://doi.org/10.1016/j.physbeh.2021.113370
Soto M, Cai W, Konishi M, Kahn CR (2019) Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci U S A 116:6379–6384. s://doi.org/10.1073/pnas.1817391116
Inamori KI, Inokuchi JI (2020) Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights. Int J Mol Sci 21:5349. s://doi.org/10.3390/ijms21155349
Cole AA, Dosemeci A, Reese TS (2010) Co-segregation of AMPA receptors with G(M1) ganglioside in synaptosomal membrane subfractions. Biochem J 427:535–540. https://doi.org/10.1042/BJ20091344
Prendergast J, Umanah GK, Yoo SW, Lagerlöf O, Motari MG, Cole RN, Huganir RL, Dawson TM, Dawson VL, Schnaar RL (2014) Ganglioside regulation of AMPA receptor trafficking. J Neurosci 34:13246–13258. s://doi.org/10.1523/JNEUROSCI.1149-14.2014
Sukhov IB, Lebedeva MF, Zakharova IO, Derkach KV, Bayunova LV, Zorina II, Avrova NF, Shpakov AO (2020) Intranasal Administration of Insulin and Gangliosides Improves Spatial Memory in Rats with Neonatal Type 2 Diabetes Mellitus. Bull Exp Biol Med 168:317–320. https://doi.org/10.1007/s10517-020-04699-8
Itokazu Y, Fuchigami T, Morgan JC, Yu RK (2021) Intranasal infusion of GD3 and GM1 gangliosides downregulates alpha-synuclein and controls tyrosine hydroxylase gene in a PD model mouse. Mol Ther 29:3059–3071. s://doi.org/10.1016/j.ymthe.2021.06.005
Leal G, Comprido D, Duarte CB (2014) BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76 Pt C: 639–656. s://doi.org/10.1016/j.neuropharm.2013.04.005
Gold PE (2005) Glucose and age-related changes in memory. Neurobiol Aging 26 Suppl 1:S60–S64. s://doi.org/10.1016/j.neurobiolaging.2005.09.002
McNay EC, Canal CE, Sherwin RS, Gold PE (2006) Modulation of memory with septal injections of morphine and glucose: effects on extracellular glucose levels in the hippocampus. Physiol Behav 87:298–303. s://doi.org/10.1016/j.physbeh.2005.10.016
Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Ståhlberg A, Aprico K, Larsson K, Yabe T, Moons L, Fotheringham A, Davies I, Carmeliet P, Schwartz JP, Pekna M, Kubista M, Blomstrand F, Maragakis N, Nilsson M, Pekny M (2008) Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 28:468–481. s://doi.org/10.1038/sj.jcbfm.9600546
de Pablo Y, Nilsson M, Pekna M, Pekny M (2013) Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion. Histochem Cell Biol 140:81–91. s://doi.org/10.1007/s00418-013-1110-0
Wilhelmsson U, Pozo-Rodrigalvarez A, Kalm M, de Pablo Y, Widestrand Å, Pekna M, Pekny M (2019) The role of GFAP and vimentin in learning and memory. Biol Chem 400:1147–1156. s://doi.org/10.1515/hsz-2019-0199
Ashrafi G, Wu Z, Farrell RJ, Ryan TA (2017) GLUT4 Mobilization Supports Energetic Demands of Active Synapses. Neuron 93:606-615.e3. s://doi.org/10.1016/j.neuron.2016.12.020
McNay EC, Pearson-Leary J (2020) GluT4: A central player in hippocampal memory and brain insulin resistance. Exp Neurol 323:113076. s://doi.org/10.1016/j.expneurol.2019.113076
Tadi M, Allaman I, Lengacher S, Grenningloh G, Magistretti PJ (2015) Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron -Astrocyte Metabolic Coupling in Long Term Memory. PLoS One 10:e0141568. s://doi.org/10.1371/journal.pone.0141568
Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53:703–717. s://doi.org/10.1016/j.neuron.2007.01.029
Racaniello M, Cardinale A, Mollinari C, D'Antuono M, De Chiara G, Tancredi V, Merlo D (2010) Phosphorylation changes of CaMKII, ERK1/2, PKB/Akt kinases and CREB activation during early long-term potentiation at Schaffer collateral-CA1 mouse hippocampal synapses. Neurochem Res 35:239–246. s://doi.org/10.1007/s11064-009-0047-0
Martínez-Mármol R, Chai Y, Conroy JN, Khan Z, Hong SM, Kim SB, Gormal RS, Lee DH, Lee JK, Coulson EJ, Lee MK, Kim SY, Meunier FA (2023) Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory. J Neurochem 165:791–808. s://doi.org/10.1111/jnc.15767
Hernandez F, Lucas JJ, Avila J (2013) GSK3 and tau: two convergence points in Alzheimer's disease. J Alzheimers Dis 33 Suppl 1:S141–S44. s://doi.org/10.3233/JAD-2012-129025
Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis 44:897–906. s://doi.org/10.3233/JAD-141791
Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, Dahl D, Caulder E, Neth B, Montine TJ, Jung Y, Maldjian J, Whitlow C, Friedman S (2017) Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis 57:1325–1334. s://doi.org/10.3233/JAD-161256
Avgerinos KI, Kalaitzidis G, Malli A, Kalaitzoglou D, Myserlis PG, Lioutas VA (2018) Intranasal insulin in Alzheimer's dementia or mild cognitive impairment: a systematic review. J Neurol 65:1497–1510. s://doi.org/10.1007/s00415-018-8768-0
Derkach KV, Bogush IV, Berstein LM, Shpakov AO (2015) The Influence of Intranasal Insulin on Hypothalamic-Pituitary-Thyroid Axis in Normal and Diabetic Rats. Horm Metab Res 47:916–924. s://doi.org/10.1055/s-0035-1547236