Neuroscientist. 2002 Dec;8(6):586-95.
Matrix metalloproteinases and neuroinflammation in multiple sclerosis.
Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes.
Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barré, and multiple sclerosis (MS).
The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB).
They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin.
During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons.
Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS.
Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect.
Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis.
Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.
PMID: 12467380 [PubMed - indexed for MEDLINE]
N Engl J Med. 1998 Jan 29;338(5):278-85.
Axonal transection in the lesions of multiple sclerosis.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L.
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis.
Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.
Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.
Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
Demyelinating diseases--new pathological insights, new therapeutic targets. [N Engl J Med. 1998]
PMID: 9445407 [PubMed - indexed for MEDLINE] Free full text
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