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

• Published in: International journal of developmental neuroscience 2009-06, Vol.27 (4), p.377-383
• Main Authors: Sinha, Rohit A., Khare, Priyanka, Rai, Asit, Maurya, Shailendra Kumar, Pathak, Amrita, Mohan, Vishwa, Nagar, Geet Kumar, Mudiam, Mohana Krishna Reddy, Godbole, Madan M., Bandyopadhyay, Sanghamitra
• Format: Article
• Language: English
• Subjects: AKT; Animals; Animals, Newborn; Apoptosis - drug effects; Bax; bcl-2-Associated X Protein - metabolism; Bcl‐2; Bcl‐xL; Brain - drug effects; Brain - embryology; Brain - growth & development; Caspase; Cerebellum - drug effects; Cerebellum - pathology; Cerebellum - physiology; Dietary Fats; Dietary Supplements; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Fatty Acids, Omega-3 - administration & dosage; Fatty Acids, Omega-3 - pharmacology; Female; Humans; Hypothyroidism - chemically induced; Hypothyroidism - pathology; Hypothyroidism - physiopathology; In Situ Nick-End Labeling; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; Male; p38 Mitogen-Activated Protein Kinases - metabolism; Pregnancy; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Wistar; Thyroid Hormones - metabolism
• ISSN: 0736-5748; 1873-474X
• DOI: 10.1016/j.ijdevneu.2009.02.003

Inadequate maternal intake of omega‐3‐fatty acids (ω3 FAs) causes adverse neurodevelopmental outcome in the progeny; however, their molecular mechanism of action is obscure. Since ω3 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 ω3 FAs during cerebellar development. ω3 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 ω3 FA‐supplementation significantly reduced DNA fragmentation and caspase‐3 activation in developing cerebellum of hypothyroid pups. The protection provided by ω3 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. ω3 FAs increased the levels of anti‐apoptotic proteins like Bcl‐2 and Bcl‐extra large (Bcl‐xL), known to be repressed in hypothyroidism. ω3 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 ω3 FAs in developing brain that involves regulation of apoptotic signaling pathways under stress.