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Updated: May 24, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Myelin loss associated with neuroinflammation in hypertensive rats
Fakhreya Y Jalal1, Yi Yang, Jeffrey Thompson
1Department of Neurology, MSC10 5620, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Background And Purpose:
Small vessel disease is the major cause of white matter injury in patients with vascular cognitive impairment. Matrix metalloproteinase (MMP)-mediated inflammation may be involved in the white matter damage with oligodendrocyte (Ol) death. Therefore, we used spontaneously hypertensive stroke-prone rats to study the role of neuroinflammation in white matter damage.
Methods:
Permanent unilateral carotid artery occlusion was performed at 12 weeks of age in spontaneously hypertensive stroke-prone rats. Following surgery, rats were placed on a Japanese permissive diet and received 1% NaCl in drinking water. MRI, histology, biochemistry, and ELISA characterized white matter lesions, and cognitive impairment was tested by Morris water maze.
Results:
White matter damage was observed 4 to 5 weeks following permanent unilateral carotid artery occlusion/Japanese permissive diet. Immunoblotting showed marked reduction in myelin basic protein and upregulation of immature Ols. Mature Ols underwent caspase-3-mediated apoptosis. Morris water maze showed cognitive impairment. Abnormally appearing vessels were observed and surrounded by inflammatory-like cells. IgG extravasation and hemorrhage, indicating blood-brain barrier (BBB) disruption, was closely associated with MMP-9 expression. Lesions in white matter showed reactive astrocytosis and activated microglia that expressed tumor necrosis factor-α. MMP-3 and MMP-9 were significantly increased, and MMP-2 was reduced in both astrocytes and Ol.
Conclusions:
We found apoptosis of mature Ols with an increase in immature Ols. Increased MMP-3, MMP-9, and tumor necrosis factor-α were associated with myelin breakdown and BBB disruption. Neuroinflammation is an important factor in white matter damage and Ol death, and studies using this new model can be performed to assess agents to block inflammation.
Insights
Neuroinflammation causes white matter damage and oligodendrocyte death in stroke-prone rats, leading to cognitive impairment. Matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor-alpha (TNF-α) are key factors in this process.
Area of Science:
- Neuroscience
- Pathology
- Biochemistry
Background:
- Small vessel disease is a primary cause of white matter injury in vascular cognitive impairment.
- Matrix metalloproteinase (MMP)-mediated inflammation is implicated in white matter damage and oligodendrocyte (Ol) death.
Purpose of the Study:
- To investigate the role of neuroinflammation in white matter damage using spontaneously hypertensive stroke-prone rats.
Main Methods:
- Induction of permanent unilateral carotid artery occlusion in rats.
- Assessment of white matter lesions and cognitive function using MRI, histology, biochemistry, ELISA, and Morris water maze.
- Analysis of myelin basic protein, oligodendrocyte apoptosis, and inflammatory markers.
Main Results:
- White matter damage, myelin breakdown, and cognitive impairment were observed post-occlusion.
- Mature oligodendrocytes underwent apoptosis, while immature oligodendrocytes increased.
- Blood-brain barrier disruption, associated with MMP-9, and increased MMP-3, MMP-9, and tumor necrosis factor-α were evident.
Conclusions:
- Neuroinflammation significantly contributes to white matter damage and oligodendrocyte death.
- Increased MMP-3, MMP-9, and TNF-α are linked to myelin breakdown and blood-brain barrier disruption.
- This rat model is valuable for evaluating anti-inflammatory agents for white matter injury.
