Skip to main content


Log in

Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript


Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer’s disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn+2-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca2+ that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others


Download references


We thank the Pulmonary Research Group at the University of Alberta for access to ICW instrumentation and technical assistance with experiments utilizing this technique. We also thank Dr. K. Ballanyi for assistance with calcium imaging experiments. This research was supported by grants from the University Hospital Foundation (FoMD/UHF Medical Grants competition) and Canadian Institutes of Health Research (CIHR MOP 93601 to JHJ).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jack H. Jhamandas.

Electronic supplementary material

Below is the link to the electronic supplementary material.


Supplementary Fig. 1 Gelatin zymogram showing histamine-induced upregulation of Pro-MMP-9 production was not blocked in a concentration-dependent manner following 24 h pre-incubation with H2R (Ranitidine HCl) and H3R (Clobenpropit HCl) antagonists (2.5–100 µM dose range) (EPS 4463 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, A., Vasanthan, V., Fu, W. et al. Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype. Brain Struct Funct 221, 1845–1860 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: