Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease

Abstract

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.

Burn-induced distant organ injury in rats and the effect of minocycline

“…As reported, minocycline also possesses potent anti-apoptotic properties. It inhibits caspase 1 and 3 expressions and directly blocks cytochrome c release from mitochondria [10,33]. Recent studies have shown that anti-inflammatory and immunomodulatory actions of minocycline are not related to its antimicrobial property [34].…”

“…Minocycline is a semi-synthetic second-generation tetracycline with anti-apoptotic, immunosuppressive and anti-inflammatory actions in various pathological states including acne vulgaris, periodontitis, rheumatoid arthritis, asthma, scleroderma, Parkinson's disease and Huntington's disease [7][8][9][10]. Underlying mechanisms of minocycline's anti-inflammatory actions which are independent from its main clinical use as an antimicrobial, include the inhibition of ROS, and cytokine production, interference with protein synthesis and modulation of matrix metalloproteinase activity [11,12].…”

“…Endotoxin and other bacterial-end products which become evident in the circulation as a result of burn wound colonization may activate macrophages and neutrophils. This leads to the release of oxidants, arachidonic acid metabolites, proteases, etc, which cause further injury in distant organs [1][2][3][4][5][6].Minocycline is a semi-synthetic second-generation tetracycline with anti-apoptotic, immunosuppressive and anti-inflammatory actions in various pathological states including acne vulgaris, periodontitis, rheumatoid arthritis, asthma, scleroderma, Parkinson's disease and Huntington's disease [7][8][9][10]. Underlying mechanisms of minocycline's anti-inflammatory actions which are independent from its main clinical use as an antimicrobial, include the inhibition of ROS, and cytokine production, interference with protein synthesis and modulation of matrix metalloproteinase activity [11,12].…”

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

“…, which affect the calcium homeostatic mechanism [139] and lead to deleterious consequences. Imbalance in the calcium homeostasis has been previously reported in different HD mice [140][141][142] that it is in agreement with consistent changes in the expression levels of many Ca 2+ signaling proteins [143].…”

Differential effects of early postinjury treatment with neuroprotective drugs in a mouse model using diffuse reflectance spectroscopy

“…Previous studies have revealed that minocycline successfully reduced brain damage and inflammation, protected against neurogenerative diseases, and improved cognitive functioning. 12,90 As a second alternative to minocycline, it can be argued that HTS had a positive effect on the brain as it mitigated further deterioration of injury. Finally, in comparison to other drug treatments, it is clear that notable differences exist with morphine and mannitol, as both drugs failed to recover hemodynamic parameters.…”