Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Abstract

Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNAdependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 a and caspase 12 activation induced by amyloid b peptide 1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 a were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid b peptide 1-42 -infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid b peptide 1-42 -infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 a is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

“…During aging, microglia and astrocytes, the two major cell effectors contribute to chronic activation of neuroinflammation, overexpression of proinflammatory cytokines, and reactive oxygen species. Animal studies show that inhibiting astrocytic activation using antiinflammatory minocycline can alleviate the hepatectomy-related long-term impairment of spatial memory in 19-month-old C57BL/6 mice (Jin et al 2014) and improves cognitive impairment in AD models (Choi et al 2007). Astrocytes become highly reactive in response to neuroinflammation, and the activation of astrocytes is characterized by hypertrophy and cell proliferation, which is associated with GFAP hyper-expression (Eng et al 2000).…”

The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities

“…Nonetheless, there is ample data to suggest minocycline may be a suitable treatment option for AD. In one study by Choi et al, the authors reported that minocycline administration improved behavior deficits in A infused rats [38]. Minocycline also has been shown to improve behavioral deficits while reducing the level of microglial activation in a mouse of model cerebral microvascular amyloid, although there was no apparent reduction in A another study using transgenic mice harboring the human APPsw and V717F mutations, treatment with minocycline had a positive effect on reducing microglial activation but did not attenuate A APP mice [40].…”

Inhibitory modulation of the mitochondrial permeability transition by minocycline

“…Originally developed as an antibiotic with a broad-spectrum antibacterial activity, it shows biological effects, which are fundamentally different from its antimicrobial action. 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].…”