Matrix metalloproteinase (MMP)‐12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice

Abstract

We investigated the role of matrix metalloproteinases (MMPs) in a mouse model of intracerebral haemorrhage (ICH). Transcripts encoding nine of the 23 known mammalian MMPs were measured. MMP-12 levels were the most elevated. To evaluate the role of MMP-12 in ICH, haemorrhages were induced in wild-type (WT) and MMP-12 null mice. The results show that MMP-12 null mice exhibited significant functional recovery of forelimb reaching and reduced dependence on the ipsilateral forelimb compared to WT mice. There was also a trend for improved sensory function in the tape removal test. With respect to single pellet skilled reaching, MMP-12 null mice recovered to a level that was not significantly different from sham at 14 and 28 days post-ICH. In contrast, WT animals demonstrated a persistent impairment relative to sham controls throughout the survival period (P < 0.05). The cylinder task revealed a lesion-induced reliance on the ipsilateral forelimb that was apparent at day 7 in both MMP-12 null and WT mice (P < 0.05), but only persisted in WT mice at 14 days post-ICH (P < 0.05). Differences in functional outcome could not be explained by tissue sparing. However, Iba1 immunostaining indicated that more cells bearing macrophage morphology were recruited to the lesion area in WT mice. This is the first study to profile the expression patterns of a number of the known MMPs following ICH in mice. The data indicate that MMP-12 expression following haemorrhagic stroke is deleterious and contributes to the development of secondary injury in this disease.

Mouse Intracerebral Hemorrhage Models Produce Different Degrees of Initial and Delayed Damage, Axonal Sprouting, and Recovery

“…26,27 As in the present study, the cylinder test of forelimb function shows a very modest cylinder effect in cICH in rats 28 or a short-term effect in cICH in mice. 29 Some of the effects of bICH and cICH in the mouse are distinct to that seen in the rat. Behavioral deficits persist for a greater period in rat cICH 26,30 than in the mouse.…”

Targeting MMPs in Acute and Chronic Neurological Conditions

“…For example, in EAE, transcripts encoding 11 of 20 MMPs were significantly elevated in the spinal cord at peak disease compared with controls. 42 Multiple MMPs are also increased in the early periods after spinal cord trauma, 43,44 intracerebral hemorrhage [45][46][47] and ischemic strokes. 48,49 As the CNS encounters most MMPs only in low amounts in the normal situation, the concurrent and significant increase of multiple MMPs with the potential for widespread proteolysis must have undue consequences.…”

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

“…Our previous report 45 revealed that the levels of all MMP members analyzed did not differ between naïve wild-type or MMP-12 Ϫ/Ϫ mice, or when these mice were subjected to an intracerebral hemorrhage insult. We determined if this was also the case in EAE-afflicted mice.…”

“…In previous work, we found that the levels of all MMP members analyzed did not differ between naïve wild-type or MMP-12 Ϫ/Ϫ mice. 45 EAE was induced in female wild-type, OPN Ϫ/Ϫ , MMP-12 Ϫ/Ϫ , or OPN/MMP-12 Ϫ/Ϫ mice on C57BL/6 background, aged 8 to 9 weeks, by subcutaneously injecting 100 g myelin oligodendrocyte glycoprotein (MOG) in Complete Freund's Adjuvant (Difco Laboratories, Detroit, MI). Intraperitoneal pertussis toxin (0.4 g/200 l; List Biological Labs, Hornby, ON) was administered on days 0 and 2.…”