Table 5.

Studies in experimental animals on the effects of the omega-3 polyunsaturated fatty acids (PUFA) in the thyroid setting. *

Reference	Aims and animals studied	Main findings
Soukup (137)	To review whether i) administration of n-3 PUFA could improve thyroid hormone (TH)-induced pathophysiological changes such as cardiac tissue remodeling and cell-to-cell communication changes, skeletal muscle protein alterations, alterations in the expression of protein kinases, oxidative stress markers, and cell death, mitochondrial functions, changes in serum lipid levels, in activities of key enzymes of TH metabolism and acetylcholine esterase or membrane anisotropy, as well as in thermal sensitivity and mobile behavior.	Soukup et al. think that there is a rationale for n-3 PUFA administration being capable to ameliorate TH-induced pathophysiological changes in settings such as cardiac disorders. For instance, n-3 PUFA intake significantly reduced cardiovascular risk factors, as they suppressed the incidence of ventricular fibrillation and facilitated sinus rhythm restoration in spontaneously hypertensive rats (SHR) in the early and late stages of hypertension. The antiarrhythmic effects of n-3 PUFA can be attributed to the attenuation of abnormal myocardial gap junction protein connexin 43 (Cx43) distribution, expression, and phosphorylation, as well as to positive modulation of PKCϵ and PKCδ signaling and normalization of myosin heavy chain (MyHC) profiles. Indeed, intercellular Cx43 gap junction channels are involved in the increased susceptibility of the heart to arrhythmias caused by increased TH levels; the expression of PKCϵ, which directly phosphorylates Cx43, is affected.
Sinha et al. (138)	A murine model of hypothyroidism-induced neuronal apoptosis was used to investigate the role of omega-3-fatty acids (ω-3 FAs) in regulating neuronal apoptosis during brain development. Pregnant and lactating rats with methimazole-induced primary hypothyroidism were supplemented with a mixture of EPA and DHA. Apoptosis was studied on cerebella from postnatal day 16 (d16) pups.	In the hypothyroid pups, Ω-3 FA-supplementation did not significant. The percentages of DHA and EPA in total cerebellar FAs increased significantly in the ω-3 FA-treated hypothyroid pups compared to euthyroid pups (Ep) and untreated hypothyroid pups (UHp). The cerebellar weight of ω-3 FA-treated hypothyroid pups was similar to that of Ep and greater than that of UHp. In the developing cerebellum of the hypothyroid pups, Ω-3 FA-supplementation decreased significantly DNA fragmentation and caspase-3. The protection given by ω-3 FAs was associated with their ability to prevent increased levels of pro-apoptotic basal cell lymphoma protein-2 (Bcl-2)-associated X protein (Bax) in the cerebellum during hypothyroidism. Ω-3 FAs increased the levels of anti-apoptotic proteins like Bcl-2 and Bcl-extra-large (Bcl-x(L)), which were low in UHp. Ω-3 FAs also restored levels of cerebellar phospho (p)-AKT, phospho-c-Jun N-terminal kinase (p-JNK), and phospho-extracellular regulated kinase (p-ERK), which were low in UHp. In sum, data support the anti-apoptotic role of ω-3 FAs during cerebellar development.
Pal et al. (139)	To study the effects of iodine and n-3 fatty acids [FA]), separately and together, in the progeny of an iodine-deficient (ID) pregnant rat model. The supplementation diets were: (i) low-iodine diet (LID), (ii) LID+potassium iodide (KI), (iii) LID+n-3 FA, and (iv) LID+KI+n-3 FA. Morphological and biochemical parameters at the peak of cerebellar histogenesis on postnatal day 16 (P16) and for both neurobehavioural and motor coordination parameters at P40 were studied.	n-3 FA significantly improved morphological, functional and biochemical indices of the developing cerebellum, despite no improvement in circulating thyroid hormone levels. Co-supplementation with n-3 FA and iodine rescued the loss of neurotrophic support, and salvaged motor coordination, learning and memory. This additive effect resulted in significantly improving neurotrophic support and seemed to be mediated by parallel significant increase in TH receptor (TR)α and normalization of TRβ, p75 neurotrophin receptor and retinoic orphan receptor α, as well as prevention of apoptosis and strengthening of anti-oxidative defense. Thus, n-3 FA may play an important mitigating role in iodine deficiency in enhancing TH nuclear receptor-mediated signaling in the developing cerebellum.
Abd Allah et al. (140)	To study the effect of hypothyroidism on memory and spatial learning in adult male rats (n= 30), the underlying mechanisms and the possible therapeutic value of omega-3 supplementation. Rats were divided into three groups; hypothyroid, omega-3 treated and controls.	Omega-3 supplementation increased serum total antioxidant capacity, decreased the structural changes of the hippocampus (diffuse vacuolar degeneration and distortion of the pyramidal cells), and decreased the expression of Cav1.2 (the voltage-dependent LTCC alpha 1c subunit) protein, and improved memory deficits. Thus, omega-3 could be useful neuroprotective agents against the cognitive impairment caused by hypothyroidism.
Gomaa et al. (141)	To investigate, in adult male rats, (i) the hyperthyroidism-induced hepatic dysfunction (ii) whether such dysfunction could be ameliorated by the administration of omega-3 on hyperthyroidism-induced hepatic dysfunction, and (iii) the underlying mechanisms of this ameliorative effect. Rats (n= 24) were divided into three groups; control (which received water for 6 weeks), hyperthyroid (which received L-T4 orally for 6 weeks) and hyperthyroid omega-3 treated (which received L-T4 for 2 weeks and then co-treated with L-T4 and an omega-3 oral mixture of EPA+DHA for 4 weeks).	The hyperthyroid omega-3 treated group had significantly increased final body weight and body weight gain, decreased liver weight to body weight ratio, decreased serum T3 level, increased serum TSH level, decreased serum levels of transaminases, and TNFα, decreased hepatic levels of total peroxide and IL-1β and increased hepatic levels of total antioxidant capacity when compared with the hyperthyroid group. Liver histopathology also confirmed marked improvement of the lesions caused by hyperthyroidism. In brief, omega-3 has encouraging therapeutic effects against hyperthyroidism-induced hepatic dysfunction. These effects can be attributed to multiple mechanisms: anti-inflammatory, antioxidant, and anti-fibrotic effects.
Rauchová et al. (142)	To investigate whether a 6-week supplementation with n-3 PUFA (200 mg/kg of body weight/day intragastrically) would affect lipid metabolism in Lewis male rats with altered thyroid status.	Supplementation of n-3 PUFA did not significantly modify plasma lipid levels in any thyroid status. Also, n-3 PUFA did not modify thyroid dysfunction-induced altered plasma glucose levels.
Awumey et al. (143)	To evaluate some heart parameters in hypothyroid rats and euthyroid controls that had received diets enriched in either n-6 or n-3 fatty acids (FA).	In hypothyroid animals fed the n-3 diet, maximum tension was 105% greater than resting compared to 399% in controls. Similar responses to noradrenaline and adrenaline were observed, that is, maximum tension was significantly greater in both hypothyroid and euthyroid rats fed the n-3 diet, but the tension was depressed in the hypothyroid rats. Binding of the β-adrenoceptor antagonist [3H]-dihydroalprenolol to ventricular membranes had high affinity and was saturable, regardless of thyroid status and diet. However, binding affinity (Kd) was higher in hypothyroid rats fed the n-6 diet. The inotropic response to forskolin was the same in hypothyroid animals, regardless of diet, but the maximum developed tension was significantly greater in euthyroid rats fed the n-6 compared to the n-3 diet. The dose-response curve for forskolin was shifted to the right in hypothyroid rats fed the n-3 diet, indicating decreased sensitivity. In sum, the depressed contractility of the hypothyroid heart may be attributed in part to an altered lipid environment of the β-adrenoceptor complex. Moreover, n-3 FA supplementation can significantly increase maximum developed tension in the hypothyroid state.

*Keywords of relevance are highlighted by the bold-face print.