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There are important postnatal changes in the sino-atrial node (SAN), the pacemaker of the heart. Compared with the neonate, the adult has a slower intrinsic heart rate and a longer SAN action potential. These changes may be due to differences in ion channel expression. Consequently, we investigated postnatal developmental changes in the expression of ion channels and Ca 2+ -handling proteins in the SAN to see whether this is indeed the case. Using quantitative PCR, in situ hybridization and immunohistochemistry, we investigated the expression of ion channels, Ca 2+ -handling proteins and connexins in the SAN from neonatal (2-7 days of age) and adult (∼6 months of age) New Zealand White rabbits. The spontaneous beating rate of adult SAN preparations was 21% slower than that of neonatal preparations. During postnatal development, quantitative PCR revealed a significant decline in the SAN of the following mRNAs: HCN4 (major isoform responsible for I f ), Na V 1.5 (responsible for I Na ), Ca V 1.3 (in part responsible for I Ca,L ) and NCX1 (responsible for inward I NaCa ). These declines could be responsible for the slowing of the pacemaker during postnatal development. There was a significant decline during development in mRNA for delayed rectifier K + channel subunits (K V 1.5, responsible for I K,ur , K V LQT1 and minK, responsible for I K,s , and ERG, responsible for I K,r ) and this could explain the prolongation of the action potential. In situ hybridization confirmed the changes observed by quantitative PCR. In addition, immunohistochemistry revealed hypertrophy of nodal cells during postnatal development. Moreover, there were complex changes in the expression of Ca 2+ -handling proteins with age. In summary, there are significant postnatal changes in the expression of ion channels and Ca 2+ -handling proteins in the SAN that could explain the established changes in heart rate and action potential duration that occur during normal development.

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Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy.

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Thyroid hormones and omega-3 are essential for normal brain functions. Recent studies have suggested that omega-3 may protect against the risk of dementia. The aim of this study was to investigate the effect of hypothyroidism on spatial learning and memory in adult male rats, the underlying mechanisms and the possible therapeutic value of omega-3 supplementation. Thirty male rats were divided into three groups; control, hypothyroid and omega-3 treated. Hypothyroidism induced significant deficits in working and reference memories in radial arm maze, retention deficits in passive avoidance test and impaired intermediate and long-term memories in novel object recognition test. Serum total antioxidant capacity (TAC) and hippocampal serotonin and γ-aminobutyric acid (GABA) levels were decreased in the hypothyroid group as compared to the control group. Moreover, the hippocampus of hypothyroid rats showed marked structural changes as diffuse vacuolar degeneration and distortion of the pyramidal cells. Immunohistochemistry showed that the expression of Cav1.2 (the voltage dependent LTCC alpha 1c subunit) protein was increased in the hypothyroid group as compared to the control group. Omega-3 supplementation ameliorated memory deficits, increased TAC, decreased the structural changes and decreased the expression of Cav1.2 protein. In conclusion omega-3 could be useful as a neuroprotective agent against hypothyroidism-induced cognitive impairment.Keywords: hypothyroidism, cognition, omega-3, Cav1.2, GABA and serotonin Thyroid hormones play an important role in the development and the normal function of CNS by different mechanisms. They regulate synaptic transmission (15), modulate the synthesis and turnover of neurotransmitters and modify the sensitivity of their receptors (42, 51). They modulate signal transduction pathways in the CNS through Ca 2+ channels. L-type voltagesensitive Ca 2+ (Cav) channel (L-VSCC) mediates long lasting Ca 2+ currents (55) that play important roles in neurotransmitters release, second messenger cascades and gene regulation (28). L-VSCCs localize prominently on neuronal cell bodies and proximal dendrites (24). They consist of five subunits: α1, α2, β, γ and δ (40); α1 subunit is the ion-conducting pore and contains the binding sites for dihydropyridine (9). There are two different L-VSCC α1 subunits: α1C (Cav1.2) and α1D (Cav1.3) (47). Growing evidence has suggested that excessive Ca 2+ influx through L-VSCCs may be detrimental to memory (55). Moreover, L-VSCC currents were reported to be increased in the hippocampus of aged rats and rabbits and thus, had been implicated in aged-related memory deficits (50). Omega-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are major components of neuronal membranes and have a wide range of functions including neural growth (18), neuroprotection and modulation of

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