N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma

• N-acetylcysteine amide (NACA) is a novel antioxidant therapy for spinal trauma.
• NACA acutely preserved synaptic, non-synaptic and total mitochondrial bioenergetics.
• Continuous NACA delivery over 24 h preserved mitochondrial glutathione levels.
• Prolonged NACA treatment increased long-term tissue sparing and functional recovery.

Mitochondrial dysfunction is becoming a pivotal target for neuroprotective strategies following contusion spinal cord injury (SCI) and the pharmacological compounds that maintain mitochondrial function confer neuroprotection and improve long-term hindlimb function after injury. In the current study we evaluated the efficacy of cell-permeating thiol, N-acetylcysteine amide (NACA), a precursor of endogenous antioxidant glutathione (GSH), on mitochondrial function acutely, and long-term tissue sparing and hindlimb locomotor recovery following upper lumbar contusion SCI. Some designated injured adult female Sprague–Dawley rats (n = 120) received either vehicle or NACA (75, 150, 300 or 600 mg/kg) at 15 min and 6 h post-injury. After 24 h the total, synaptic, and non-synaptic mitochondrial populations were isolated from a single 1.5 cm spinal cord segment (centered at injury site) and assessed for mitochondrial bioenergetics. Results showed compromised total mitochondrial bioenergetics following acute SCI that was significantly improved with NACA treatment in a dose-dependent manner, with maximum effects at 300 mg/kg (n = 4/group). For synaptic and non-synaptic mitochondria, only 300 mg/kg NACA dosage showed efficacy. Similar dosage (300 mg/kg) also maintained mitochondrial GSH near normal levels. Other designated injured rats (n = 21) received continuous NACA (150 or 300 mg/kg/day) treatment starting at 15 min post-injury for one week to assess long-term functional recovery over 6 weeks post-injury. Locomotor testing and novel gait analyses showed significantly improved hindlimb function with NACA that were associated with increased tissue sparing at the injury site. Overall, NACA treatment significantly maintained acute mitochondrial bioenergetics and normalized GSH levels following SCI, and prolonged delivery resulted in significant tissue sparing and improved recovery of hindlimb function.