Pharmacological Modulation of Glutamatergic and Neuroinflammatory Pathways in a Lafora Disease Mouse Model

Mollá, Belén; Heredia, Miguel López de; Campos, Angela Machado de; Sanz, Pascual

doi:10.1007/s12035-022-02956-7

Cited by 7 publications

(12 citation statements)

References 69 publications

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“…The order of the behavioral tests and resting time between them were the same for each mouse. The selected battery of behavioral tests was based on the results obtained in previous reports for the use of Epm2b-/- mice [ 20 , 21 ]. It consisted of three tests performed in the following order: hindlimb clasping, open field, and object location memory (OLM).…”

Section: Methodsmentioning

confidence: 99%

“…The samples in paraffin were sagittal sectioned at 4 µm using a microtome. The presence of polyglucosans (PGs) inclusions (the hallmark of Lafora disease) in Epm2b -/- mice was assessed by periodic acid Schiff (PAS) staining as detailed in [ 20 ] and [ 21 ]. Six mice (3 females and 3 males) were analyzed in total per each group (WT or Epm2b-/- untreated and Epm2b-/- treated with fingolimod or dimethyl fumarate).…”

Section: Methodsmentioning

confidence: 99%

“…Most of the results described above have been obtained by using LD knockout (KO) mouse models of LD with a complete loss of function of laforin ( Epm2a-/- ) [ 16 ] or malin ( Epm2b-/- ) [ 17 ]. These animals partially mimic human symptoms such as early accumulation of PGs in brain and peripheral tissues, abnormal postures of the hindlimb, memory defects, and hyperactivity with disrupted attention [ 16 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

Rubio,

Campos-Rodríguez,

Sanz

2023

Mol Neurobiol

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Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimethyl fumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethyl fumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

Rubio,

Campos-Rodríguez,

Sanz

2023

Mol Neurobiol

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“…The order of the behavioral tests and resting time between them were the same for each mouse. The selected battery of behavioral tests was based on the results obtained in previous reports for the use of Epm2b-/-mice [20], [21]. It consisted of three tests performed in the following order: hindlimb clasping, open eld, and object location memory (OLM).…”

Section: Behavioral Testsmentioning

confidence: 99%

“…The samples in para n were sagittal sectioned at 4 μm using a microtome. The presence of polyglucosans (PGs) inclusions (the hallmark of Lafora disease) in Epm2b-/mice, was assessed by periodic acid Schiff (PAS) staining as detailed in [20], [21]. Six mice (3 females and 3 males) were analyzed in total per each group (WT or Epm2b-/untreated and Epm2b-/treated with ngolimod or dimetylfumarate).…”

Section: Tissue Collection and Histopathological Analysesmentioning

confidence: 99%

Beneficial effect of fingolimod in a Lafora disease mouse model by preventing reactive astrogliosis-derived neuroinflammation and brain infiltration of T-lymphocytes.

Rubio

Campos-Rodríguez

Sanz

2023

Preprint

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Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimetylfumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethylfumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests.

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Lafora progressive myoclonus epilepsy: Disease mechanism and therapeutic attempts

Parihar,

Ganesh

2024

J Biosci

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Pharmacological Modulation of Glutamatergic and Neuroinflammatory Pathways in a Lafora Disease Mouse Model

Cited by 7 publications

References 69 publications

Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

Beneficial effect of fingolimod in a Lafora disease mouse model by preventing reactive astrogliosis-derived neuroinflammation and brain infiltration of T-lymphocytes.

Lafora progressive myoclonus epilepsy: Disease mechanism and therapeutic attempts

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