Liposome-encapsulated clodronate and COX-2 inhibitor treatment impair ventilatory recovery but improve compensatory locomotor function following cervical spinal cord injury in rats

Abstract

Over half of all spinal cord injuries (SCIs) in the United States occur at the cervical level and can cause locomotor deficits and life-threatening breathing dysfunction. Interestingly, the bisphosphonate drug clodronate has shown efficacy in ameliorating tissue damage and improving locomotor recovery acutely after experimentally induced thoracic SCI. Thus, we hypothesized that clodronate treatment would improve recovery of breathing and locomotor function following a C2 hemisection (C2Hx) model of cervical SCI in rats. Serendipitously, changes to animal use guidelines led to the inclusion of carprofen, a non-steroidal anti-inflammatory drug (NSAID), as another independent variable in our study. We treated adult rats intravenously with either liposomal clodronate or saline via the tail vein at days 1, 3, and 6 post-C2Hx. Carprofen treatment was administered subcutaneously on days 0, 1, and 2 post-injury. We used whole-body plethysmography to measure ventilatory function and the semi-automated CatWalk® gait analysis system to assess locomotor function through 4 weeks post-SCI. Contrary to our initial hypothesis, we found that both liposomally encapsulated clodronate and carprofen impaired ventilatory recovery following C2Hx. However, in alignment with our hypothesis, clodronate improved locomotor function on the side contralateral to injury. To reconcile these seemingly conflicting outcomes, we propose that clodronate treatment may exacerbate lung inflammation, altering peripheral-to-central modulation of respiratory output—highlighting that the effects of these treatments may be specific to injury level and target organ system. By further elucidating clodronate and carprofen as clinically relevant therapeutics, the work described here serves to advance efforts to improve care for individuals living with SCI