Anti‐apoptotic role of omega‐3‐fatty acids in developing brain: perinatal hypothyroid rat cerebellum as apoptotic model

Abstract

Inadequate maternal intake of omega-3-fatty acids (omega3 FAs) causes adverse neurodevelopmental outcome in the progeny; however, their molecular mechanism of action is obscure. Since omega3 FAs are known to inhibit neuronal apoptosis during neuro-degeneration, we investigated their possible contribution in regulating neuronal apoptosis during brain development. Using rat model of hypothyroidism-induced neuronal apoptosis, we provide evidence for anti-apoptotic role of omega3 FAs during cerebellar development. omega3 FAs were supplemented as a mixture of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to pregnant and lactating rats, and primary hypothyroidism was induced by administering methimazole. The cerebella from postnatal day 16 (d16) pups were isolated, and studies on apoptosis were conducted. We observed that omega3 FA-supplementation significantly reduced DNA fragmentation and caspase-3 activation in developing cerebellum of hypothyroid pups. The protection provided by omega3 FAs was associated with their ability to prevent increases in the level of pro-apoptotic basal cell lymphoma protein-2 (Bcl-2)-associated X protein (Bax) in the cerebellum during thyroid hormone (TH) deficiency. omega3 FAs increased the levels of anti-apoptotic proteins like Bcl-2 and Bcl-extra large (Bcl-x(L)), known to be repressed in hypothyroidism. omega3 FAs also restored levels of cerebellar phospho (p)-AKT, phospho-extracellular regulated kinase (p-ERK) and phospho-c-Jun N-terminal kinase (p-JNK), which were altered by hypothyroid insults, without interfering with the expression of TH responsive gene, myelin basic protein (mbp). Taken together, these results supplement an insight into the molecular mechanism of action of omega3 FAs in developing brain that involves regulation of apoptotic signaling pathways under stress.

Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina

“…For inducing hypothyroidism, 2-mercapto-1-methylimidazole (MMI) (0.025%, w/v) was given from G5 in drinking water and continued until P-60 in the control rats (Sinha et al, 2009).…”

“…The SDS-PAGE and Westernblotting was performed following an optimized protocol (Sinha et al, 2009) with MBP, PLP, CNPase, MAG, NF, Brn3b or GFAP (1:1000) and β-actin-antibodies (1:2000), followed with anti-rabbit or anti-mouse IgG conjugated to horseradish-peroxidase. The samples were detected by chemiluminescence with super signal west-femto-max-substrate.…”

Meta-analysis of heat- and chemically upregulated chaperone genes in plant and human cells

“…Possibly, the use of various NSAID combinations, together with other of CSR-chaperone-inducing drugs, such as hydroxylamine derivatives (Vigh et al 1997), vanilloids, such as curcumin (Kanitkar and Bhonde 2008), flavonoids, such as quercetin (Aalinkeel et al 2008), or omega-3-fatty acids (Narayanan et al 2006), with anti-aging and anti-apoptotic effects on developing brain (Sinha et al 2009), may improve protein misfolding diseases and aging in general (Gidalevitz et al 2010). Combinations of non-toxic HSP drugs could directly decrease the cellular concentration of cytotoxic protein conformers and indirectly block neuroinflammation and apoptosis signals, leading to an arrest of tissue loss.…”

n-3 Fatty Acid-Derived Lipid Mediators against Neurological Oxidative Stress and Neuroinflammation

“…Eicosanoidindependent proapoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis, and enhanced production of reactive oxygen species (ROS), as well as activation of p53. In the brain, DHA also restores levels of cerebellar phospho (p)-AKT, phospho-extracellular regulated kinase (p-ERK) and phospho-c-Jun N-terminal kinase (p-JNK), supporting their role in downregulation of neuronal apoptosis (Sinha et al, 2009). DHA also quenches gene expression of cyclooxygenase-2 and other enzymes, thereby diminishing the formation of pro-inflammatory eicosanoids.…”