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Advanced Neurology Targets and medications for AVM of CNS

of BAVMs . Twelve BAVM patients were recruited and which has been shown to be correlated with ICH in
[46]
were treated with minocycline or doxycycline (200 mg/day) BAVMs . Therefore, the repair of vascular mural cells has
[51]
for up to 2 years. The results of their follow-up suggested been considered a potential treatment strategy for BAVMs
that patients with BAVMs are able to tolerate minocycline in recent years [49,50] .
and doxycycline well; however, their results failed to show This hypothesis was mainly inspired by the efficacy
any trend toward potential patient benefit because one of thalidomide for patients with HHT, as shown in a
BAVM ruptured during the treatment. In another study, study where the platelet-derived growth factor-B/platelet-
Burrows et al. used marimastat, another MMP inhibitor, derived growth factor receptor (PDGF-B/PDGF-R)
for the treatment of a young girl with multiple AVMs signaling pathway was upregulated and mural cells were
involving the upper extremities . Following the treatment recruited following thalidomide intervention in mice .
[47]
[52]
with marimastat, the young girl experienced pain relief, A series of clinical investigations have confirmed that oral
and there was healing of bony destruction; however, thalidomide could significantly protect against epistaxis and
newly formed AVMs were observed during the treatment. gastrointestinal hemorrhage caused by telangiectasias [53,54] .
Therefore, although the rationale of anti-inflammation From pathological and genetic points of view, telangiectasias
therapy is justified and commended, there has been no and AVMs are distinct lesions. However, the key pathological
solid evidence showing that it may benefit patients with feature of telangiectasia is also the expansion of capillaries
AVMs of the CNS. Table 2 shows different clinical studies with pericyte coverage reduction. The previous studies have
of MMP inhibitors according to timeline. revealed that thalidomide can enhance pericyte coverage in
telangiectasia by enhancing the expression of PDGF-B in
2.3. Vascular integrity
endothelial cells . The PDGF-B/PDGF-R signaling pathway
[52]
The results of emerging studies have suggested that plays a key role in recruiting mural cells. During angiogenesis,
BAVM rupture is associated with a maldeveloped vascular endothelial cell paracrine PDGF-B and its receptor PDGF-R
wall structure [48-50] . Compared with healthy cerebral are mainly expressed in the precursors of pericytes and
vasculature, the BAVMs in both human and mouse models vascular smooth muscle cells . Although no compelling
[52]
are characterized by abnormal vessels lacking mural cells studies have found an impairment of the PDGFB/PDGFR
(vascular smooth muscle cells and pericytes), which are signaling pathway in sporadic AVMs, the above findings still
similar to engorged and expanded capillaries . With indicate that thalidomide may be a promising candidate for
[49]
insights into the physiological function of mural cells, the pharmacological treatment of brain and spinal AVMs.
the above pathological features of AVMs may represent To the best of our knowledge, thalidomide has not been
impaired vascular integrity and a tendency for rupture. investigated in patients with brain or spinal AVMs. A major
As expected, clinical pathological investigations have concern about the use of thalidomide in AVM patients is
indicated that these thin-walled vessels are the source of its rare and frequent toxicities, such as teratogenicity and
microhemorrhage and subsequent inflammatory reaction, peripheral neuropathy . In addition, a relapse of epistaxis
[55]
Table 2. Clinical Study of MMP Inhibitors.

Medication Target Publication Phase Dosage Duration Number Objective Result Side effect
of cases
Doxycycline MMP-9 Hashimoto - 100 mg, One week 14 Investigate decreased MMP-9 Not displayed
et al., 2005 [22] twice a day doxycycline in AVM tissues
effect for
MMP-9
Minocycline MMP-9 Frenzel et al. - 100 mg, Two years 26 Evaluate Similar adverse Dose-limiting intolerance
Doxycycline 2008 [46] twice a day feasibility event rates were occurred in 31%
recorded minocycline and 23%
doxycycline patients
Marimastat MMP Burrows - 30-120 mg, Several 1 Case report of Pain relieved, No adverse effects
Doxycycline et al., 2009 [47] 100 mg, years treatment effect and recurrence of
daily symptoms appeared
Doxycycline MMP-9 Lindeman - 50/100/300 2 weeks 60 Evaluate vascular Short and selective Not displayed
et al., 2009 [43] mg, daily inflammation inhibitory effect on
level inflammation was
recorded
–: Phase not mentioned in the article or belonging to any of them, AVM: Arteriovenous malformation, MMP-9: Matrix metalloproteinase-9

Volume 1 Issue 3 (2022) 4 https://doi.org/10.36922/an.v1i3.211