Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury

Abstract

We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at Ϸ4 -8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg͞kg administered 1 h after SCI followed by 45 mg͞kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2 ,3 cyclic nucleotide 3 phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

“…Teng et al . (2004) have shown that spinal cord injury (SCI) increases mitochondrial cytochrome c release and minocycline treatment provides neuroprotective effect by reducing cytochrome c release in SCI. These data suggest that therapeutic regulation of mitochondrial function may be an effective approach to treat neurotrauma.…”

Inhibitory modulation of the mitochondrial permeability transition by minocycline

“…An increasing number of studies reported the potential use of MC as a cytoprotectant in the treatment of several neurological disorders including amyotropic lateral scerosis [2], multiple sclerosis [3], Alzheimer's disease [4], Huntigton's disease [5], Leber's hereditary optic neuropathy [6], and Parkinson's disease (PD) [7][8][9]. Furthermore, neuroprotective potency of MC has been observed in experimental models of acute cerebral ischemia [10,11], spinal cord- [12][13][14] and traumatic brain injury [15]. But, also contradictory and even detrimental effects of MC were reported recently [16][17][18][19][20], pointing at the importance of a thorough understanding of the detailed cellular and molecular mechanisms triggered by MC.…”

Oligodendrocyte Fate after Spinal Cord Injury

“…Thus, numerous therapeutic strategies have been tested to increase post-SCI OL survival. Several studies have shown that the anti-inflammatory agent minocycline promotes white matter sparing and OL protection after SCI, in part by inhibiting microglial production of pro-NGF [146][147][148]. Lee et al [149] showed that methylprednisolone, a common treatment after SCI, protected OLs, but not neurons by blocking apoptosis.…”