MRI of Neuronal Recovery after Low-Dose Methamphetamine Treatment of Traumatic Brain Injury in Rats

Guang Liang Ding,Quan Jiang,John S Budaj,Hongtao Wu,Michael Chopp,Siamak P Nejad-Davarani,David J Poulsen,Qingjiang Li,Asim Mahmood,Lian Li,Changsheng Qu

doi:10.1371/journal.pone.0061241

Guang Liang Ding, Quan Jiang + Show 9 more

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https://doi.org/10.1371/journal.pone.0061241

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Abstract

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T2 maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky’s silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84±1.41%) compared with the control group (17.05±2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery.

Highlights

Traumatic brain injury (TBI) is a leading factor of morbidity and mortality in Western countries [1,2], and an important public health problem
Methamphetamine treatment did not significantly reduce lesion volumes compared to the controls during 6 weeks after TBI in rats, and the lesion volumes are quantitated in Fig. 2 a
This study demonstrated that low dose methamphetamine treatment starting at 8 hours after traumatic insult in rats significantly improved the recovery of behavioral functions in rats by lowering modified neurological severity scores (mNSS) and foot-fault scores after TBI, compared with saline treatment

Summary

Introduction

Traumatic brain injury (TBI) is a leading factor of morbidity and mortality in Western countries [1,2], and an important public health problem. There is an urgent need to develop a novel approach for the treatment of TBI, that can restore brain function. TBI produces a primary insult, which may trigger widespread brain damage regardless of the original site of injury [3]. The management of patients with TBI to-date has primarily focused on therapeutic intervention designed to reduce cellular damage and brain edema [9]; currently, no effective clinical treatment can repair biostructural damage to the neurons and prevent or reduce secondary pathological processes [10]. Experimental pharmacological and cell-based treatments of TBI which promote brain remodeling have shown promising results in improving functional recovery after TBI in animals [11,12,13,14,15]

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