Development of Cardiovascular Dysfunction in a Rat Spinal Cord Crush Model and Responses to Serotonergic Interventions

Abstract

Selection of a proper spinal cord injury (SCI) rat model to study therapeutic effects of cell transplantation is imperative for research in cardiovascular functional recovery, due to the local harsh milieu inhibiting cell growth. We recently found that a crushed spinal cord lesion can minimize fibrotic scarring and grafted cell death compared with open-dura injuries. To determine if this SCI model is applicable for studying cardiovascular recovery, we examined hemodynamic consequences following crushed SCI and tested cardiovascular responses to serotonin (5-HT) or dopamine (DA) receptor agonists. Using a radio-telemetric system, multiple cardiovascular parameters were recorded prior to, 2, and 4 weeks after SCI, including resting mean arterial pressure (MAP) and heart rate (HR), as well as spontaneous or colorectal distension (CRD)-induced autonomic dysreflexia (AD). The results showed that this injury caused tachycardia at rest as well as the occurrence of spontaneous or artificially induced dysreflexic events. Four weeks post-injury, specific activation of 5-HT 2A receptors by subcutaneous (s.c.) or intrathecal (i.t.) delivery of Dimethoxy-4-iodoamphetamine (DOI) remarkably increased resting MAP levels in a dose-dependent fashion. During CRD-induced autonomic dysreflexia, systemic administration of DOI alleviated the severity of bradycardia responsive to episodic hypertension. In contrast, selective stimulation of 5-HT 1A receptors with 8-OH-DPAT or non-selective activation of DA receptors with apomorphine did not affect cardiovascular performance. Thus, crush injuries induce cardiovascular abnormalities in rats that are sensitive to 5-HT 2A receptor stimulation, indicating a reliable SCI model to study how cell-based approaches impact the severity of autonomic dysreflexia and identify a possible target for pharmacological interventions.

Grafting Embryonic Raphe Neurons Reestablishes Serotonergic Regulation of Sympathetic Activity to Improve Cardiovascular Function after Spinal Cord Injury

“…Nonetheless, we cannot directly rule out the possibility that viable cells within the graft produced abundant 5-HT that diffused into CSF (Tadepalli et al, 1977), allowing for longer-distance transport to SPNs. Since recent studies found that stimulating spinal 5-HT 2A receptors improves basal hemodynamic and reflexes in SCI rats (Cormier et al, 2010;Trueblood et al, 2019), excess 5-HT in the CNS may maintain a certain degree of cardiovascular performance after serotonergic projections are interrupted.…”

“…After administration of ketanserin, CRD elicited only a subtle pressor response in all three groups of injured animals. This may be due to the necessity of these receptors for sympathetic reflexes or peripheral responses (Danzebrink and Gebhart, 1991;Trueblood et al, 2019). Therefore, we then turned to retransecting the spinal cord below the injury to evaluate the role of RN-NSC grafts in the improved cardiovascular function we observed.…”

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

“…Superficial laminae and lamina X [17] Antinociception, pronociception [17] Micturition [398,399] SCH 23390 [398][399][400]402,403], SCH 39166 [401,404] Aripiprazole [405], apomorphine [300,398,400,406], SKF 83959…”

Development of a Spinal Cord Injury Model Permissive to Study the Cardiovascular Effects of Rehabilitation Approaches Designed to Induce Neuroplasticity

“…Loss of supraspinal 5-HT + fibres play a key role in inducing CV dysregulation including contributing to the development of AD and hypotension observed post-SCI [33,48]. Other models of SCI which have explored the relationship between 5-HT + preservation and CV function post-SCI include complete crush [25], and partial transection [49] models of SCI at the T4 level. Neither crush injury nor partial transection reported reduced MAP despite showing reduced/absent density of serotonergic fibres caudal to the injury.…”

“…For the CV system, a number of rat models have been developed to study the CV consequences of SCI, as well as the efficacy of various therapeutics. Two of the models that have received most traction are the T3/T4 complete transection model or a very severe midline contusion injury [23,24], though others also exist [25]. Both transection and severe contusion injuries (i.e., 400 kdyn contusion model) have been effective in producing changes to the CV function that mimic those observed clinically with high-lesion SCI, such as the presence of pronounced hypotension, reduced systolic cardiac function, and the presence of autonomic dysreflexia and orthostatic intolerance [23,[26][27][28][29].…”