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Review
. 2016 Dec 15;17(12):2107.
doi: 10.3390/ijms17122107.

α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions

Patrizia Ambrogini  1 , Michele Betti  2 , Claudia Galati  3 , Michael Di Palma  4 , Davide Lattanzi  5 , David Savelli  6 , Francesco Galli  7 , Riccardo Cuppini  8 , Andrea Minelli  9
Affiliations
Review

α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions

Patrizia Ambrogini et al. Int J Mol Sci. .

Abstract

Neuroplasticity is an "umbrella term" referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular α-tocopherol (α-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/α-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/α-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity.

Keywords: adult neurogenesis; brain; development; neuroplasticity; seizures; vitamin E.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phosphorylation of protein kinase C (PKC) and PKC substrates are reduced in developing hippocampus of α-tocopherol-exposed pups. (A) PKCpan, PKCα and PKCδ phosphorylation in the hippocampus of developing offspring and PKCpan phosphorylation in the hippocampus of adult offspring; (B) Phosphorylation of PKC substrates GAP-43 and MARCKS in the hippocampus of developing and adult offspring. Hippocampal protein extracts taken from CTRL and TREAT developing and adult offspring (at each time point, for each group, n = 8 animals from four different litters) were subjected to SDS/PAGE (12% polyacrylamide for PKCpan, PKCα, PKCδ and GAP-43 and 7% polyacrylamide for MARCKS) followed by Western blotting, using polyclonal phospho-specific antibody directed to PKCpan, PKCα, PKCδ, GAP-43 and MARKS. Histograms represent densitometric analyses of blots from three independent experiments (means ± S.E.M.). Representative CTRL value is shown as dashed line. Relative decreases in band absorbance values (arbitrary units) were normalized for the control band in each series. Student’s t test: * p < 0.05. Figure modified from [78]. GAP: growth associated protein; MARCKS: myristoylated alanine-rich C-kinase substrate; CTRL: control, untreated; TREAT: treated.
Figure 2
Figure 2
α-Tocopherol treatment decreases hippocampal neuroinflammation in kainate-induced status epilepticus. (A) GFAP (glial fibrillary acidic protein) immunoreactivity expressed as percent of area fluorescence; (B) GS (glutamine synthetase) immunoreactivity expressed as percent of area fluorescence; (C) Branch point number of Iba1 (ionized calcium-binding adapter molecule 1)-positive microglial cells; (D) Process length of Iba1-positive microglial cells; (E) Western blotting analysis of neuroinflammatory markers GFAP, MHC II, IL-1β and TNF-α in hippocampus protein extracts obtained from CTRL and TREAT rats. Representative non-epileptic and untreated animals’ value is shown as dashed line. Statistical analyses performed by one-way ANOVA and Tukey’s post hoc test: * p < 0.05; ** p < 0.01. CTRL: kainate-exposed untreated rats. TREAT: kainate-exposed α-tocopherol treated rats. Figure modified from [276]. MHC II: major histocompatibility complex II; IL-1β, interleukin 1 β; TNF-α: tumor necrosis factor α.
Figure 2
Figure 2
α-Tocopherol treatment decreases hippocampal neuroinflammation in kainate-induced status epilepticus. (A) GFAP (glial fibrillary acidic protein) immunoreactivity expressed as percent of area fluorescence; (B) GS (glutamine synthetase) immunoreactivity expressed as percent of area fluorescence; (C) Branch point number of Iba1 (ionized calcium-binding adapter molecule 1)-positive microglial cells; (D) Process length of Iba1-positive microglial cells; (E) Western blotting analysis of neuroinflammatory markers GFAP, MHC II, IL-1β and TNF-α in hippocampus protein extracts obtained from CTRL and TREAT rats. Representative non-epileptic and untreated animals’ value is shown as dashed line. Statistical analyses performed by one-way ANOVA and Tukey’s post hoc test: * p < 0.05; ** p < 0.01. CTRL: kainate-exposed untreated rats. TREAT: kainate-exposed α-tocopherol treated rats. Figure modified from [276]. MHC II: major histocompatibility complex II; IL-1β, interleukin 1 β; TNF-α: tumor necrosis factor α.
Figure 3
Figure 3
Effect of α-tocopherol treatment on hippocampal neurodegeneration induced by status epilepticus. (A) Degenerating neurons quantified as FluorJade-positive cells along rostro-caudal extension of CA1 field; (B) Neurofilament immunoreactivity expressed as percent of area fluorescence; (C) Dendritic spine number quantified per unit length of dendrite; (D) Synaptophysin immunoreactivity expressed as percent of area fluorescence. Statistical analyses performed by (A) Student’s t test: ** p < 0.01 and (B–D) one-way ANOVA and Tukey’s post hoc test: * p < 0.05; ** p < 0.01. Figure modified from [276].
Figure 4
Figure 4
α-Tocopherol treatment per se affects neuroinflammation in non-epileptic rats. (A) TNF-α western blotting quantification in hippocampus protein extracts of CTRL and TREAT rats: TNF-α was significantly reduced following α-tocopherol treatment in the absence of seizures; (B) Process length of Iba1-positive microglial cells: The graph shows a significantly longer microglial processes, indicating the influence of α-tocopherol in determining microglia morphology and activity in normal rats. Statistical analyses performed by one-way ANOVA and Tukey’s post hoc test: ** p < 0.01. TREAT: non epileptic α-tocopherol-treated rats. CTRL: non epileptic rats’ untreated rats. Figure modified from [276].
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