Potential Role of Hypercoagulation in the Onset and Progression of Obesity Induced Neurodegeneration

Aims: The mechanisms explaining the trigger of obesity driven neurodegeneration are not well elucidated. Hypercoagulation followed by hypofibrinolysis mark the pivotal events in the advent of neurodegeneration in obesity. However, the contribution of coagulation mediators in obesity linked neurodegeneration remains unknown.&nbsp;In this study&nbsp;the role of hypercoagulation in obesity induced neurodegeneration in&nbsp;high cholesterol diet (HCD) fed wistar&nbsp;rats&nbsp;has been evaluated. <br><br>Main methods: Wistar rats were fed a high cholesterol diet (HCD) in three different concentrations for eight weeks.&nbsp; Body weight, lipid profile and coagulation markers were assessed every alternate week (0 th &nbsp;week, 2nd&nbsp;week, 4th week, 6th&nbsp;week and 8th&nbsp;week) till eight weeks. Neurodegeneration in HCD fed groups was compared with STZ-ICV administered rats. Analysis included quantification of: (i) body weight, lipid profile, oxidative stress, inflammatory response; (ii) the contribution of the coagulation mediators (PT, aPTT, fibrinogen) and fibrinolytic activity; and (iii) neuropathological changes, neurodegeneration and behavioural response. <br><br>Key findings: Parallel rise in body weight, cholesterol level and coagulation mediators was observed in HCD fed rats during 8 weeks of study. Significant increase ROS production and levels of inflammatory markers including TNF-α, IL-6, NF-kβ was observed in HCD fed rats. Our results also reflected that significant alterations in platelet count, coagulation markers and fibrinolytic activity in HCD fed rats are suggestive of the potential link between obesity, hypercoagulation and neurodegeneration. Further, histopathological analysis, done through H&amp;E and Congo red staining, demonstrated apoptosis and amyloidogenic effects in the hippocampus of HCD fed rats. IHC analysis showed reduced levels of neuronal growth factors VEGF and BDNF although behavioural changes were significant only in the group with highest concentration of cholesterol as assessed by Morris water maze test. <br><br>Significance: Our findings highlight the potential contribution of hypercoagulation followed by hypofibrinolysis in the onset and progression of neurodegeneration in diet induced obesity.<br><br>Funding Information: ndian Council of Medical Research (ICMR), Government of India, India.<br><br>Conflict of Interests: The authors declare that they have no conflict of interest.<br><br>Ethical Approval: The experimental protocol was approved by Institutional Animal Ethics Committee of Jamia Hamdard (Hamdard University), New Delhi, India (Registration no.173/GO/ReBi/2000/CPCSEA) as per the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals.