Estudio de la ruta neurotrófica Pleiotrofina/PTPRZ en el hipocampo de ratas expuestas a consumo crónico de alcohol y/o deficiencia de tiamina Study of the Pleiotrophin/PTPRZ neurotrophic pathway in the hippocampus of rats exposed to chronic alcohol consumption and/or thiamine deficiency

Autores/as

  • Rosario López-Rodríguez Universidad San Pablo-CEU
  • Marta Moya Universidad Complutense de Madrid
  • Esther Gramage Universidad San Pablo-CEU
  • Gonzalo Herradón Universidad San Pablo-CEU
  • Laura Orio Universidad Complutense de Madrid

DOI:

https://doi.org/10.20882/adicciones.2464

Palabras clave:

Wernicke, Korsakoff, deficiencia de tiamina, pleiotrofina, receptor proteína tirosina Fosfatasa Z, neuroinflamación, hipocampo Wernicke, Korsakoff, thiamine deficiency, pleiotrophin, Protein Tyrosine Phosphatase Receptor Z, neuroinflammation, hippocampus

Resumen

La encefalopatía de Wernicke (WE) es una enfermedad neurológica causada por la deficiencia de tiamina (TD) cuyo principal factor de riesgo es el trastorno por uso del alcohol. El objetivo de este estudio es explorar el perfil de expresión de genes candidatos relacionados con neuroinflamación, disfunción mitocondrial y metabolismo de la tiamina en el hipocampo de animales expuestos a consumo crónico de alcohol (CA), una dieta deficiente en tiamina (TDD) o la combinación de ambos. Se analizaron un total de 42 ratas Wistar macho incluidas en 4 grupos experimentales: control (C) que recibieron agua o agua suplementada con tiamina (0,2 g/L), alcohol crónico (CA) durante 36 semanas, dieta TD y piritiamina durante 12 días (TDD) y un grupo que combinaba CA+TDD. La expresión relativa de factores neurotróficos (Ptn, Mdk, Ptprz), factores proinflamatorios (Tlr4, Ccl2 y Hmgb1), proteínas implicadas en homeostasis mitocondrial (Mfn1 y Mfn2) y enzimas del metabolismo de la tiamina (Tpk1) se determinó a partir de ARNm obtenido del hipocampo de los distintos grupos experimentales. El análisis estadístico se realizó mediante el test no paramétrico Kruskal-Wallis. La expresión de Ptprz tendía a ser menor en el grupo TDD comparado con el grupo C (no significativo) mientras que la disminución de Ptprz observada en el grupo TDD fue estadísticamente significativa cuando se comparaba con el grupo CA+TDD (p<0,05). Además, el grupo TDD mostró los menores niveles de expresión de Ptn y esta disminución fue estadísticamente significativa comparada con los grupos C y CA (p<0,05). Nuestros resultados indican un perfil diferencial de expresión de la ruta PTN-MDK-PTPRZ en el hipocampo de ratas con una dieta TD distinto al observado en el resto de los modelos de encefalopatía WE analizados (CA y CA+TDD).
Wernicke’s encephalopathy (WE) is caused by thiamine deficiency (TD) whose main risk factor is alcohol use disorder. Pathogenic mechanisms associated with WE include mitochondrial dysfunction, oxidative stress and neuroinflammation. This study aims to explore the gene expression signature of certain candidate genes related to neuroinflammation, mitochondrial dysfunction and thiamine metabolism in the hippocampus from animals exposed to chronic alcohol consumption, thiamine deficiency or the combination of both. Male Wistar rats (n=42) were randomly assigned to 4 experimental groups: control (C) receiving tap water or tap water plus thiamine (0.2 g/L), chronic alcohol (CA) forced ingestion for 36 weeks, TD diet and pyrithiamine for 12 days (TDD) and CA combined with TDD. The relative gene expression of neurotrophic factors (Ptn, Mdk, Ptprz), proinflammatory molecules (Tlr4, Ccl2 and Hmgb1), mitochondrial homeostatic factors (Mfn1 and Mfn2) and thiamine metabolism (Tpk1) was analyzed in RNA isolated from the hippocampus across all experimental groups. Differences in gene expression were assessed using non-parametric tests (Kruskal-Wallis). Ptprz mRNA levels tended to be downregulated in the TDD group compared to controls (p=0.06, non-significant) and levels were significantly decreased related to the CA+TDD group (p<0.05). TDD group showed the lowest expression levels of Ptn across all experimental groups, and this decrease was statistically significant compared to the control and CA groups (p<0.05). Our findings indicate a differential gene expression profile of the PTN-MDK-PTPRZ axis in the hippocampus of rats receiving a TD diet but not in the rest of the WE models analyzed (CA and CA+TDD).

Citas

Abdou, E. y Hazell, A. S. (2015). Thiamine Deficiency: An Update of Pathophysiologic Mechanisms and Future Therapeutic Considerations. Neurochemical Research, 40(2), 353–361. https://doi.org/10.1007/s11064-014-1430-z

Arts, N., Walvoort, S. y Kessels, R. (2017). Korsakoff´s syndrome: A critical review. Neuropsychiatric Disease and Treatment, Volume 13, 2875–2890. https://doi.org/10.2147/NDT.S130078

Calleja‐Conde, J., Fernández‐Calle, R., Zapico, J. M., Ramos, A., de Pascual‐Teresa, B., Bühler, K., Echeverry‐Alzate, V., Giné, E., Rodríguez de Fonseca, F., López‐Moreno, J. A. y Herradón, G. (2020). Inhibition of Receptor Protein Tyrosine Phosphatase β/ζ Reduces Alcohol Intake in Rats. Alcoholism: Clinical and Experimental Research, 44(5), 1037–1045. https://doi.org/10.1111/acer.14321

Cañeque-Rufo, H., Fontán-Baselga, T., Galán-Llario, M., Zuccaro, A., Sánchez-Alonso, M. G., Gramage, E., Ramos-Álvarez, M. del P. y Herradón, G. (2025). Pleiotrophin deletion prevents high-fat diet-induced cognitive impairment, glial responses, and alterations of the perineuronal nets in the hippocampus. Neurobiology of Disease, 205, 106776. https://doi.org/10.1016/j.nbd.2024.106776

Cassiano, L. M. G., Oliveira, M. S., Pioline, J., Salim, A. C. M. y Coimbra, R. S. (2022). Neuroinflammation regulates the balance between hippocampal neuron death and neurogenesis in an ex vivo model of thiamine deficiency. Journal of Neuroinflammation, 19(1), 272. https://doi.org/10.1186/s12974-022-02624-6

Chew, L., Takanohashi, A. y Bell, M. (2006). Microglia and inflammation: Impact on developmental brain injuries. Mental Retardation and Developmental Disabilities Research Reviews, 12(2), 105–112. https://doi.org/10.1002/mrdd.20102

Cressant, A., Dubreuil, V., Kong, J., Kranz, T. M., Lazarini, F., Launay, J.-M., Callebert, J., Sap, J., Malaspina, D., Granon, S. y Harroch, S. (2017). Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice. Psychopharmacology, 234(4), 575–587. https://doi.org/10.1007/s00213-016-4490-8

del Campo, M., Fernández-Calle, R., Vicente-Rodríguez, M., Martín Martínez, S., Gramage, E., Zapico, J. M., Haro, M. y Herradon, G. (2021). Role of Receptor Protein Tyrosine Phosphatase β/ζ in Neuron–Microglia Communication in a Cellular Model of Parkinson’s Disease. International Journal of Molecular Sciences, 22(13), 6646. https://doi.org/10.3390/ijms22136646

Eva, L., Brehar, F.-M., Florian, I.-A., Covache-Busuioc, R.-A., Costin, H. P., Dumitrascu, D.-I., Bratu, B.-G., Glavan, L.-A. y Ciurea, A. V. (2023). Neuropsychiatric and Neuropsychological Aspects of Alcohol-Related Cognitive Disorders: An In-Depth Review of Wernicke’s Encephalopathy and Korsakoff’s Syndrome. Journal of Clinical Medicine, 12(18), 6101. https://doi.org/10.3390/jcm12186101

Fernandez, G. M., Stewart, W. N. y Savage, L. M. (2016). Chronic Drinking During Adolescence Predisposes the Adult Rat for Continued Heavy Drinking: Neurotrophin and Behavioral Adaptation after Long-Term, Continuous Ethanol Exposure. PLOS ONE, 11(3), e0149987. https://doi.org/10.1371/journal.pone.0149987

Fernández-Calle, R., Galán-Llario, M., Gramage, E., Zapatería, B., Vicente-Rodríguez, M., Zapico, J. M., de Pascual-Teresa, B., Ramos, A., Ramos-Álvarez, M. P., Uribarri, M., Ferrer-Alcón, M. y Herradón, G. (2020). Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication. Scientific Reports, 10(1), 20259. https://doi.org/10.1038/s41598-020-76415-5

Fernández-Calle, R., Vicente-Rodríguez, M., Pastor, M., Gramage, E., Di Geronimo, B., Zapico, J. M., Coderch, C., Pérez-García, C., Lasek, A. W., de Pascual-Teresa, B., Ramos, A. y Herradón, G. (2018). Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase β/ζ (PTPRZ1) modulates behavioral responses to ethanol. Neuropharmacology, 137, 86–95. https://doi.org/10.1016/j.neuropharm.2018.04.027

Flatscher‐Bader, T. y Wilce, P. A. (2008). Impact of Alcohol Abuse on Protein Expression of Midkine and Excitatory Amino Acid Transporter 1 in the Human Prefrontal Cortex. Alcoholism: Clinical and Experimental Research, 32(10), 1849–1858. https://doi.org/10.1111/j.1530-0277.2008.00754.x

Galán‐Llario, M., Rodríguez‐Zapata, M., Fontán‐Baselga, T., Cañeque‐Rufo, H., García‐Guerra, A., Fernández, B., Gramage, E. y Herradón, G. (2024). Pleiotrophin Overexpression Reduces Adolescent Ethanol Consumption and Modulates Ethanol‐Induced Glial Responses and Changes in the Perineuronal Nets in the Mouse Hippocampus. CNS Neuroscience & Therapeutics, 30(12). https://doi.org/10.1111/cns.70159

Galán-Llario, M., Rodríguez-Zapata, M., Fontán-Baselga, T., Gramage, E., Vicente-Rodríguez, M., Zapico, J. M., de Pascual-Teresa, B., Lasek, A. W. y Herradón, G. (2023a). Inhibition of RPTPβ/ζ reduces chronic ethanol intake in adolescent mice and modulates ethanol effects on hippocampal neurogenesis and glial responses in a sex-dependent manner. Neuropharmacology, 227, 109438. https://doi.org/10.1016/j.neuropharm.2023.109438

Galán-Llario, M., Rodríguez-Zapata, M., Gramage, E., Vicente-Rodríguez, M., Fontán-Baselga, T., Ovejero-Benito, M.C., Pérez-García C, Carrasco J., Moreno-Herradón M, Sevillano J., Ramos-Álvarez P., Zapico, J. M., de Pascual-Teresa, B., Ramos A. y Herradón, G. (2023b). Receptor protein tyrosine phosphatase β/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure. Neurotoxicology, 94:98-107. https://doi.org/10.1016/j.neuro.2022.11.008

Gombash, S. E., Lipton, J. W., Collier, T. J., Madhavan, L., Steece-Collier, K., Cole-Strauss, A., Terpstra, B. T., Spieles-Engemann, A. L., Daley, B. F., Wohlgenant, S. L., Thompson, V. B., Manfredsson, F. P., Mandel, R. J. y Sortwell, C. E. (2012). Striatal Pleiotrophin Overexpression Provides Functional and Morphological Neuroprotection in the 6-Hydroxydopamine Model. Molecular Therapy, 20(3), 544–554. https://doi.org/10.1038/mt.2011.216

Gomez-Nicola, D. y Perry, V. H. (2015). Microglial Dynamics and Role in the Healthy and Diseased Brain. The Neuroscientist, 21(2), 169–184. https://doi.org/10.1177/1073858414530512

González-Castillo, C., Ortuño-Sahagún, D., Guzmán-Brambila, C., Pallàs, M. y Rojas-Mayorquín, A. E. (2015). Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus. Frontiers in Cellular Neuroscience, 8. https://doi.org/10.3389/fncel.2014.00443

Gramage, E., Rossi, L., Granado, N., Moratalla, R. y Herradón, G. (2010). Genetic inactivation of Pleiotrophin triggers amphetamine-induced cell loss in the substantia nigra and enhances amphetamine neurotoxicity in the striatum. Neuroscience, 170(1), 308–316. https://doi.org/10.1016/j.neuroscience.2010.06.078

Hammoud, N. y Jimenez-Shahed, J. (2019). Chronic Neurologic Effects of Alcohol. Clinics in Liver Disease, 23(1), 141–155. https://doi.org/10.1016/j.cld.2018.09.010

Han, S., Nandy, P., Austria, Q., Siedlak, S. L., Torres, S., Fujioka, H., Wang, W. y Zhu, X. (2020). Mfn2 Ablation in the Adult Mouse Hippocampus and Cortex Causes Neuronal Death. Cells, 9(1), 116. https://doi.org/10.3390/cells9010116

Herradon, G., Ezquerra, L., Nguyen, T., Silos-Santiago, I. y Deuel, T. F. (2005). Midkine regulates pleiotrophin organ-specific gene expression: Evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family. Biochemical and Biophysical Research Communications, 333(3), 714–721. https://doi.org/10.1016/j.bbrc.2005.05.160

Herradón, G. y Pérez‐García, C. (2014). Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: Recent progress and perspectives. British Journal of Pharmacology, 171(4), 837–848. https://doi.org/10.1111/bph.12312

Herradon, G., Ramos-Alvarez, M. P. y Gramage, E. (2019). Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00377

Jhala, S. S. y Hazell, A. S. (2011). Modeling neurodegenerative disease pathophysiology in thiamine deficiency: Consequences of impaired oxidative metabolism. Neurochemistry International, 58(3), 248–260. https://doi.org/10.1016/j.neuint.2010.11.019

Jung, Y. J., Tweedie, D., Scerba, M. T. y Greig, N. H. (2019). Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments. Frontiers in Cell and Developmental Biology, 7. https://doi.org/10.3389/fcell.2019.00313

Jung, Y.-C., Chanraud, S. y Sullivan, E. V. (2012). Neuroimaging of Wernicke’s Encephalopathy and Korsakoff’s Syndrome. Neuropsychology Review, 22(2), 170–180. https://doi.org/10.1007/s11065-012-9203-4

Kielian, T. (2016). Multifaceted roles of neuroinflammation: The need to consider both sides of the coin. Journal of Neurochemistry, 136(S1), 5–9. https://doi.org/10.1111/jnc.13530

Kohnke, S. y Meek, C. L. (2021). Don’t seek, don’t find: The diagnostic challenge of Wernicke’s encephalopathy. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 58(1), 38–46. https://doi.org/10.1177/0004563220939604

Lehnardt, S. (2010). Innate immunity and neuroinflammation in the CNS: The role of microglia in Toll‐like receptor‐mediated neuronal injury. Glia, 58(3), 253–263. https://doi.org/10.1002/glia.20928

Li, S. y Xing, C. (2025). Wernicke encephalopathy: A mini review of the clinical spectrum, atypical manifestations, and diagnostic challenges. Frontiers in Neurology, 16. https://doi.org/10.3389/fneur.2025.1566366

Livak, K. J. y Schmittgen, T. D. (2001). Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods, 25(4), 402–408. https://doi.org/10.1006/meth.2001.1262

Maeda, N., Ichihara-Tanaka, K., Kimura, T., Kadomatsu, K., Muramatsu, T. y Noda, M. (1999). A Receptor-like Protein-tyrosine Phosphatase PTPζ/RPTPβ Binds a Heparin-binding Growth Factor Midkine. Journal of Biological Chemistry, 274(18), 12474–12479. https://doi.org/10.1074/jbc.274.18.12474

Martin, P. R., Singleton, C. K. y Hiller-Sturmhöfel, S. (2003). The role of thiamine deficiency in alcoholic brain disease. Alcohol Research & Health : The Journal of the National Institute on Alcohol Abuse and Alcoholism, 27(2), 134–142.

McCoy, M. K. y Cookson, M. R. (2012). Mitochondrial quality control and dynamics in Parkinson’s disease. Antioxidants & Redox Signaling, 16(9), 869–882. https://doi.org/10.1089/ARS.2011.4019

Mira, R. G., Lira, M., Quintanilla, R. A. y Cerpa, W. (2020). Alcohol consumption during adolescence alters the hippocampal response to traumatic brain injury. Biochemical and Biophysical Research Communications, 528(3), 514–519. https://doi.org/10.1016/j.bbrc.2020.05.160

Moya, M., Escudero, B., Gómez-Blázquez, E., Rebolledo-Poves, A. B., López-Gallardo, M., Guerrero, C., Marco, E. M. y Orio, L. (2022a). Upregulation of TLR4/MyD88 pathway in alcohol-induced Wernicke’s encephalopathy: Findings in preclinical models and in a postmortem human case. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.866574

Moya, M., López-Valencia, L., García-Bueno, B. y Orio, L. (2022b). Disinhibition-Like Behavior Correlates with Frontal Cortex Damage in an Animal Model of Chronic Alcohol Consumption and Thiamine Deficiency. Biomedicines, 10(2), 260. https://doi.org/10.3390/biomedicines10020260

Moya, M., San Felipe, D., Ballesta, A., Alén, F., Rodríguez de Fonseca, F., García-Bueno, B., Marco, E. M. y Orio, L. (2021). Cerebellar and cortical TLR4 activation and behavioral impairments in Wernicke-Korsakoff Syndrome: Pharmacological effects of oleoylethanolamide. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 108, 110190. https://doi.org/10.1016/j.pnpbp.2020.110190

Oscar-Berman, M. y Maleki, N. (2019). Alcohol Dementia, Wernicke’s Encephalopathy, and Korsakoff’s Syndrome. En M. L. Alosco & R. A. Stern (Eds.), The Oxford Handbook of Adult Cognitive Disorders (pp. 742–758). Oxford University Press. https://doi.org/10.1093/oxfordhb/9780190664121.013.33

Rodríguez-Zapata, M., Galán-Llario, M., Cañeque-Rufo, H., Sevillano, J., Sánchez-Alonso, M. G., Zapico, J. M., Ferrer-Alcón, M., Uribarri, M., Pascual-Teresa, B. de, Ramos-Álvarez, M. del P., Herradón, G., Pérez-García, C. y Gramage, E. (2023). Implication of the PTN/RPTPβ/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS. Biomedicines, 11(5), 1318. https://doi.org/10.3390/biomedicines11051318

Rodríguez-Zapata, M., López-Rodríguez, R., Ramos-Álvarez, M. del P., Herradón, G., Pérez-García, C. y Gramage, E. (2024). Pleiotrophin modulates acute and long-term LPS-induced neuroinflammatory responses and hippocampal neurogenesis. Toxicology, 509, 153947. https://doi.org/10.1016/j.tox.2024.153947

Ross-Munro, E., Kwa, F., Kreiner, J., Khore, M., Miller, S. L., Tolcos, M., Fleiss, B. y Walker, D. W. (2020). Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury. Frontiers in Neurology, 11. https://doi.org/10.3389/fneur.2020.568814

Sahu, P., Verma, H. K. y Bhaskar, L. (2025). Alcohol and alcoholism associated neurological disorders: Current updates in a global perspective and recent recommendations. World Journal of Experimental Medicine, 15(1). https://doi.org/10.5493/wjem.v15.i1.100402

Toledo Nunes, P., Vedder, L. C., Deak, T. y Savage, L. M. (2019). A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol‐Related Brain Damage. Alcoholism: Clinical and Experimental Research, 43(3), 425–438. https://doi.org/10.1111/acer.13946

van Horssen, J., van Schaik, P. y Witte, M. (2019). Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders? Neuroscience Letters, 710. https://doi.org/10.1016/J.NEULET.2017.06.050

Vicente‐Rodríguez, M., Pérez‐García, C., Ferrer‐Alcón, M., Uribarri, M., Sánchez‐Alonso, M. G., Ramos, M. P. y Herradón, G. (2014). Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol. Journal of Neurochemistry, 131(5), 688–695. https://doi.org/10.1111/jnc.12841

Vicente-Rodríguez, M., Rojo Gonzalez, L., Gramage, E., Fernández-Calle, R., Chen, Y., Pérez-García, C., Ferrer-Alcón, M., Uribarri, M., Bailey, A. y Herradón, G. (2016). Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation. European Neuropsychopharmacology, 26(11), 1794–1805. https://doi.org/10.1016/j.euroneuro.2016.09.002

Wai, T. y Langer, T. (2016). Mitochondrial Dynamics and Metabolic Regulation. Trends in Endocrinology and Metabolism: TEM, 27(2), 105–117. https://doi.org/10.1016/J.TEM.2015.12.001

Xia, Y., Qian, T., Fei, G., Cheng, X., Zhao, L., Sang, S. y Zhong, C. (2024). Low expression of thiamine pyrophosphokinase-1 contributes to brain susceptibility to thiamine deficiency. NeuroReport, 35(15), 1000–1009. https://doi.org/10.1097/WNR.0000000000002094

Zahr, N. M., Alt, C., Mayer, D., Rohlfing, T., Manning-Bog, A., Luong, R., Sullivan, E. V. y Pfefferbaum, A. (2014). Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke’s encephalopathy. Experimental Neurology, 261, 109–119. https://doi.org/10.1016/j.expneurol.2014.06.015

Zhao, Y., Wu, Y., Hu, H., Cai, J., Ning, M., Ni, X. y Zhong, C. (2014). Downregulation of transketolase activity is related to inhibition of hippocampal progenitor cell proliferation induced by thiamine deficiency. BioMed Research International, 2014, 572915. https://doi.org/10.1155/2014/572915

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2025-12-23

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Vol. 37 Núm. 4 (2025)

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