Somatostatin blockade of CNS autonomic hyperactivity for treatment of diabetic retinopathy

我们已经证明，生长抑素(SST)在下丘脑的表达缺失是 脑干交感神经自主神经效应器的慢性兴奋性激活 糖尿病中的神经元。我们有证据表明，脑室周围下丘脑SST神经元(即 那些支配脑干交感神经的神经)直接支配骨髓(BM) 保护这一数量不多但很重要的种群似乎对预防 交感神经亢进。交感神经过度活动导致骨髓功能障碍 促炎性单核细胞的产生和释放有助于疾病的发展 糖尿病视网膜病变(DR)。骨髓功能障碍引起的系统性单核细胞增多症也有助于 促进下丘脑和脑干交感神经自主神经炎症 效应神经元导致自主神经兴奋的自动持续循环。 这些研究得出的中心假设是，恢复SST水平和 糖尿病患者下丘脑的神经元活动达到非糖尿病患者的水平将降低慢性 脑干交感自主神经效应神经元的兴奋性激活，避免 骨髓病理学的发展与随后的全身和视网膜炎症 导致了Dr。 在目标1中，我们将确定SST神经元活动的丧失是否会导致持续性 下丘脑脑干自主神经效应核团的过度兴奋与慢性过度激活 导致BM病理的BM。在目标2中，我们将确定是否恢复海温 使用载体表达SST的糖尿病啮齿动物下丘脑神经元表达水平将降低 交感神经元对骨髓的慢性过度激活，预防/逆转骨髓 功能障碍与防治博士在目标3中，我们将测试长期药理是否 使用生长抑素类似物奥曲肽鼻腔给药的补充将 预防糖尿病引起的骨髓功能障碍和DR，阻断下丘脑炎症停止 自主神经兴奋的自动持续周期。SST类似物已经被 在人类中进行了广泛的测试，这种策略可以立即转化为临床使用，通过 采用SST类似物鼻腔给药降低糖尿病交感神经 多动与骨髓病理、全身性炎症和DR有关。

We have shown that loss of somatostatin (SST) expression in the hypothalamus is associated with chronic excitatory activation of brainstem sympathetic autonomic effector neurons in diabetes. We have evidence that periventricular hypothalamic SST neurons (i.e. those that innervate brainstem sympathetics) directly innervate bone marrow (BM) and that preservation of this small, but important population appears to be particularly relevant to prevent sympathetic hyperactivity. Sympathetic hyperactivity leads to BM dysfunction with an increase in the generation and release of proinflammatory monocytes that contribute to the development of diabetic retinopathy (DR). Systemic monocytosis resulting from BM dysfunction also serves to promote neuroinflammation of the hypothalamus and of brainstem sympathetic autonomic effector neurons resulting in an auto-perpetuating cycle of excitation of autonomic neurons. The central hypothesis emerging from these studies is that restoring SST levels and neuronal activity in the diabetic hypothalamus to nondiabetic levels will reduce chronic excitatory activation of brainstem sympathetic autonomic effector neurons, avoid development of BM pathology and the subsequent systemic and retinal inflammation leading to DR. In Aim 1, we will determine whether loss of SST neuronal activity results in persistent hypothalamic hyper excitation of brainstem autonomic effector nuclei and chronic over activation of the BM leading to BM pathology. In Aim 2, we will determine whether restoration of SST levels using vector expressing SST in hypothalamic neurons of diabetic rodents will reduce chronic over activation of sympathetic neuronal activity to the BM, prevent/reverse BM dysfunction and prevent/treat DR. In Aim 3, we will test whether long-term pharmacological supplementation using intranasal delivery of the somatostatin analogue, octreotide, would prevent diabetes-induced BM dysfunction and DR, and block hypothalamic inflammation to stop the auto-perpetuating cycle of excitation of autonomic neurons. SST analogues have been tested extensively in humans and this strategy could be immediately translated to clinical use by adopting intranasal administration of SST analogues to reduce diabetes-induced sympathetic hyperactivity responsible for BM pathology, systemic inflammation and DR.