Metabolic and Hematological Changes Following Traumatic Brain Injury in Sickle Cell Mice
Authors: Rao Sohan , Parchuri Ektha , Carlson Shaun W 
Published: December 2024

Introduction: Sickle cell disease (SCD) is a group of genetically inherited disorders of hemoglobin impacting ~100,000 individuals in the United States. By young adulthood, 53% of patients with SCD show radiographic evidence of silent cerebral infarction, which potentiates progressive ischemia and cognitive decline because of cumulative effects of silent cerebral infarctions secondary to recurrent vaso-occlusion and chronic hemolysis. In the context of traumatic brain injury (TBI), individuals with SCD likely face an elevated risk of complications, potentially leading to poor recovery, motor deficits, and even mortality. However, there remains a large knowledge gap in the mechanistic understanding or clinical guidelines addressing the pathophysiology of TBI in patients with SCD. To our knowledge, this is the first preclinical pilot study of the interaction between SCD and TBI.

Methods: Six hemizygote mice (6 Berkeley ɑ-/-, β-/-, Tg(HBɑ-HBBs)41Paz)/J) aged 12-18 weeks were compared with six C57BL/6J wild type (WT) mice of the same age. Each group was divided into two cohorts: one for traumatic brain injury (TBI) and one for control (n=3 per cohort). For the TBI procedure, a midline scalp incision was made, followed by a 5mm craniotomy over the left parietal cortex, located 2.7mm lateral to the midline and 2.5mm posterior to Bregma. A pneumatic impactor (Bimba, Monee, IL) with a 3 mm rounded-tipped impounder was used to deliver a controlled cortical impact (CCI) at 3.5 m/sec velocity and 1.0 mm depth at the craniotomy site. Sham control mice were anesthetized and surgically prepared but did not receive cortical impact. Righting time measured via beam balance tests serve as a proxy for vestibulomotor function. Weight, righting time, and blood gas were measured at 48 hours post-injury in SCD and WT mice.

Results: Four cohorts were compared for this study: WT-sham (n=3), WT-CCI (n=3), SCD-sham (n=3), and SCD-CCI (n=3). Assessment of weight revealed a significant difference in weights between the groups (repeated measures ANOVA, p&lt;0.05), with multiple comparisons testing revealing significantly reduced weights in Sham+SCD mice (*p&lt;0.05) and CCI+WT mice (*p&lt;0.05), as compared to Sham+WT mice. Righting times were not significantly different between groups. Measurements of pCO2 and pO2 reveal a modest difference in the group means in Sham+SCD mice from WT but was not significant. Analysis of ctHb revealed a significant reduction in Sham+SCD mice, as compared to both Sham+WT and CCI+WT mice (*p&lt;0.05). Blood gas measurements for mice could not be fully completed due to acute mortality post-TBI (n=1 CCI+SCD) and blood clotting or tail vein collection complications (n=1 Sham+WT, n=1 CCI-WT, and n=2 CCI+SCD).

Conclusion: These preliminary findings show worsened acute outcomes and diminished motor function in the SCD mice after CCI. Furthermore, while there was no significant difference in vestibulomotor function across groups in this pilot study, the contrasting hemoglobin profiles at baseline between SCD and WT mice suggest a potential predisposition to injury. This preliminary study lays the groundwork for future investigations into the pathophysiology of TBI in the context and TBI and the development of targeted clinical guidelines.