Browsing by Author "Toledo, Jorge"

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    Fish Oil Supplementation Attenuates Offspring's Neurodevelopmental Changes Induced by a Maternal High-Fat Diet in a Rat Model
    (2025) Muñoz, Yasna; Kaune, Heidy; Dagnino, Alexies; Cruz, Gonzalo; Toledo, Jorge; Valenzuela, Rodrigo; Moraga, Renato; Tabilo, Luis; Flores, Cristian; Muñoz, Alfredo; Crisosto, Nicolás; Montiel, Juan; Maliqueo, Manuel
    Background/Objectives: A maternal high-fat diet (HFD) impairs brain structure in offspring. In turn, fish oil (FO) rich in n-3 polyunsaturated fatty acids (PUFAs) has neuroprotective effects. Therefore, we investigated whether maternal HFD exposure affected the neurological reflexes, neuron morphology, and n-3 PUFA levels in the cerebral cortex of the offspring and whether these effects were mitigated by maternal FO consumption. Methods: Female Sprague Dawley rats received a control diet (CD, 10% Kcal fat) or HFD (45% Kcal fat) five weeks before mating and throughout pregnancy and lactation. From mating, a subgroup of HFD was supplemented with 11.4% FO into the diet (HFD-FO). Neurological reflexes were evaluated from postnatal day (PND) 3 until PND20. Brains were removed at PND22 for neuron morphology analysis. Moreover, fatty acid composition and transcripts of genes encoding for factors associated with synapse transmission (SNAP-25), plasticity (BDNF), transport of DHA (MFSD2a), and inflammation (NF-κB and IL-1β) were quantified in prefrontal, motor, and auditory cortices. Results: FO diminished the effects of HFD on the number of thin and mushroom-shaped dendritic spines in the cerebral cortex in both sexes. It also reversed the HFD effects on the motor and auditory reflexes in female and male offspring, respectively. In males, FO up-regulated Bdnf transcript levels in the motor cortex compared with CD and HFD. In females, n-3 PUFAs were higher in HFD and HFD-FO than in CD in the auditory cortex. Conclusions: Our results highlight the protective role of maternal dietary n-3 PUFAs in counteracting the effects induced by HFD on the acquisition of neurological reflexes and neuronal morphology in the cerebral cortex of the offspring of both sexes.
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    IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson’s disease models
    (2023) Arcos, Javiera; Grunenwald, Felipe; Sepúlveda, Denisse; Jerez, Carolina; Urbina, Valentina; Huerta, Tomas; Troncoso-Escudero, Paulina; Tirado, Daniel; Pérez, Angela; Díaz-Espinoza, Rodrigo; Nova, Esteban; Kubitscheck, Ulrich; Rodríguez-Gatica, Juan Eduardo; Hertz, Claudio; Toledo, Jorge; Ahumada, Pablo; Rojas-Rivera, Diego; Martín-Montañez, Elisa; García-Fernández, María; Vidal, René L.
    Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.

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