Anti-apoptotic role of omega-3-fatty acids in developing brain: perinatal hypothyroid rat cerebellum as apoptotic model.
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.
Sinha
Rohit A
RA
Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226001, India.
Khare
Priyanka
P
Rai
Asit
A
Maurya
Shailendra Kumar
SK
Pathak
Amrita
A
Mohan
Vishwa
V
Nagar
Geet Kumar
GK
Mudiam
Mohana Krishna Reddy
MK
Godbole
Madan M
MM
Bandyopadhyay
Sanghamitra
S
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004041:Dietary Fats; D019587:Dietary Supplements; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013963:Thyroid Hormones / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D019253:Proto-Oncogene Proteins c-bcl-2; D013963:Thyroid Hormones; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases