Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand.
The Ferrier Research Institute, Gracefield Research Centre, Victoria University of Wellington, 69 Gracefield Road, Lower Hutt 5040, New Zealand.
Int J Mol Sci. 2022 Apr 27;23(9):4817. doi: 10.3390/ijms23094817.
Stroke-induced cognitive impairments remain of significant concern, with very few treatment options available. The involvement of glycosaminoglycans in neuroregenerative processes is becoming better understood and recent advancements in technology have allowed for cost-effective synthesis of novel glycomimetics. The current study evaluated the therapeutic potential of two novel glycomimetics, compound A and G, when administered systemically five-days post-photothrombotic stroke to the PFC. As glycosaminoglycans are thought to facilitate growth factor function, we also investigated the combination of our glycomimetics with intracerebral, recombinant human brain-derived neurotrophic factor (rhBDNF). C56BL/6J mice received sham or stroke surgery and experimental treatment (day-5), before undergoing the object location recognition task (OLRT). Four-weeks post-surgery, animals received prelimbic injections of the retrograde tracer cholera toxin B (CTB), before tissue was collected for quantification of thalamo-PFC connectivity and reactive astrogliosis. Compound A or G treatment alone modulated a degree of reactive astrogliosis yet did not influence spatial memory performance. Contrastingly, compound G+rhBDNF treatment significantly improved spatial memory, dampened reactive astrogliosis and limited stroke-induced loss of connectivity between the PFC and midline thalamus. As rhBDNF treatment had negligible effects, these findings support compound A acted synergistically to enhance rhBDNF to restrict secondary degeneration and facilitate functional recovery after PFC stroke.
中风引起的认知障碍仍然是一个严重的问题，目前可用的治疗方法非常有限。糖胺聚糖在神经再生过程中的作用机制正在被深入研究，而最近技术的进步使得新型糖模拟物的经济高效合成成为可能。本研究评估了两种新型糖模拟物 A 和 G 在光血栓性中风后 5 天通过系统给药对 PFC 治疗潜力。由于糖胺聚糖被认为可以促进生长因子的功能，我们还研究了将我们的糖模拟物与脑内重组人源性脑源性神经营养因子（rhBDNF）联合使用的效果。C56BL/6J 小鼠接受假手术或中风手术和实验性治疗（第 5 天），然后进行物体位置识别任务（OLRT）。手术后 4 周，动物接受逆行示踪剂霍乱毒素 B（CTB）的前额叶内侧核注射，然后收集组织以定量测量丘脑-前额叶皮质连接和反应性星形胶质增生。单独使用化合物 A 或 G 可调节一定程度的反应性星形胶质增生，但不影响空间记忆表现。相比之下，化合物 G+rhBDNF 治疗显著改善了空间记忆，抑制了反应性星形胶质增生，并限制了中风引起的前额叶皮质和中线丘脑之间的连接丧失。由于 rhBDNF 治疗的效果可以忽略不计，这些发现支持化合物 A 与 rhBDNF 协同作用，以限制继发性变性并促进 PFC 中风后的功能恢复。
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