Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3

Abstract

In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-alpha, as well as gene expression of iNOS, TNF-alpha, IL-1beta, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

“…MMP-3 was also involved in caspase-3 activation, specifically in apoptotic signaling upstream of caspase-3 and downstream of c-Jun N-terminal kinases. 238,[241][242][243][244] Second, MMP-3 might potentially be involved in a-synuclein cleavage. Sung et al 245 showed that MMP-3 cleaves purified a-synuclein in vitro and that a-synuclein aggregation increased in the presence of MMP-3-cleaved a-synuclein fragments compared to a solution without these fragments.…”

Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin

“…By increasing ROS synthesis, it is likely to participate in the amplification of signals, leading to the activation of the MAPK pathway. Those MAPKs activate the AP-1 transcription factor and upregulate the MMPs [123]. The level of MMP-12 increases after UV exposure [124].…”

Metalloproteinases and Metalloproteinase Inhibitors in Age-Related Diseases

“…Tetracycline derivatives that penetrate the BBB, such as doxycycline and minocycline, downregulate the MMP-3 expression induced by cell stress, cytokines and other stimuli, with subsequent attenuation of neuroinflammation and apoptosis of dopaminergic neurons, both in vitro and in vivo [407][408][409][410][411]. Other compounds, such as ghrelin (an endogenous ligand for growth hormone secretagogue receptor 1a), exendin-4 (analog of glucagon-like peptide-1) or glycitein (a bacterial metabolite of the isoflavone glycitin) have also been found to attenuate MMP-3 expression, as well as loss of nigrostriatal dopaminergic neurons and hippocampal neurons [412][413][414][415].…”