3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

Pen-Sen Huang,Jia-Yi Wang,Ling-Yu Yang,Yung-Hsiao Chiang,Weiming Luo,Barry J Hoffer,Daniela Lecca,Dong Seok Kim,Ping-Yen Tsai,Nigel H Greig

doi:10.3390/ijms22158276

Abstract

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

Highlights

Traumatic brain injury (TBI) is a leading cause of injury-related death and long-term disability, with an estimated 69 million people suffering a TBI annually worldwide [1].Some 4.8 million cases occur in North America
We investigated the effectiveness of Pom and DP on hippocampal injury, neuroinflammation and neurodegeneration 7 days after a TBI
2.6%) compared to 24 h (16.2 ± 4.3%) after a TBI but we demonstrated that a single of between 5 and 7 h for a cortical impact (CCI) injury in a well-characterized rodent model of moderate intravenous injection of Pom or DP could effectively reduce the even larger contusion

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of injury-related death and long-term disability, with an estimated 69 million people suffering a TBI annually worldwide [1].Some 4.8 million cases occur in North America. Traumatic brain injury (TBI) is a leading cause of injury-related death and long-term disability, with an estimated 69 million people suffering a TBI annually worldwide [1]. The preponderance of TBIs are mild to moderate in nature, representing 80–95% of cases, with severe TBI compromising the remaining 5–20% [2,3]. TBI represents a progressive process rather than a single event. It is one of the most important risk factors for the subsequent development of neurodegenerative disorders, Parkinson’s disease and Alzheimer’s dementia [2,5], and is associated with changes in gene expressions in pathways that lead to these disorders [6,7]. The increasing incidence of TBI represents one of the largest global burdens of disease [8]

Methods

Discussion

Conclusion