Plasminogen Deficiency Causes Reduced Corticospinal Axonal Plasticity and Functional Recovery after Stroke in Mice

Abstract

Tissue plasminogen activator (tPA) has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg) into plasmin. In this study, using plasminogen knockout (Plg-/-) mice and their Plg-native littermates (Plg+/+), we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group) were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo). A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticospinal tract (CST). Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p<0.01). BDA-positive axonal density of the CST originating from the contralesional cortex in the denervated side of the cervical gray matter was significantly reduced in Plg-/- mice compared with Plg+/+ mice (p<0.05). The behavioral outcome was highly correlated with the midline-crossing CST axonal density (R2>0.82, p<0.01). Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord.

Is Remodelling of Corticospinal Tract Terminations Originating in the Intact Hemisphere Associated with Recovery following Transient Ischaemic Stroke in the Rat?

“…Furthermore, manipulating the extent of CST sprouting from the non-ischaemic hemisphere influences sensorimotor outcome. For example, blocking the neurite growth inhibitor Nogo-A after experimental stroke increases sprouting and improves performance in motor tasks [ 10 ] while knockdown of plasminogen reduces sprouting and impairs performance in motor tasks [ 11 ]. Studies of this type support the notion that the extent of sprouting in the spinal cord underpins the amount of functional recovery after stroke involving the CST.…”

Tongxinluo promotes axonal plasticity and functional recovery after stroke

“…The TXL group exhibited significant promotion of new axonal growth in the C1 area downstream of the denervated spinal cord gray matter originated from the contralesional CST, reinnervating the denervated side of the spinal cord, which may be one of the mechanisms of motor functional improvement. The contralateral CST can spontaneously project to the denervated cervical spinal cord through the midline after focal infarction induced by dMCAO surgery [ 8 , 35 , 36 , 37 ], and some studies have examined the length of the nerve fibers [ 25 ]. Herein, to study the space distribution of the BDA-positive nerve fibers, we divided the denervated gray matter into three parts (A, B, and C areas); the present study is the first to report that the TXL group had more BDA-positive nerve fibers in all three areas.…”

Physiologic variations in blood plasminogen levels affect outcomes after acute cerebral thromboembolism in mice: a pathophysiologic role for microvascular thrombosis

“…The strong dose–response relationships observed in this study provide compelling evidence for a direct effect of Pg on ischemic stroke; however, this study did not examine other molecules in the fibrinolytic pathway that also may affect outcomes. A recent stroke study suggests that Pg also has long‐term protective effects on neurologic functional recovery after stroke by affecting axonal remodeling . Although MMP‐9 expression, MMP‐3 expression and BBB breakdown are enhanced in Pg −/− mice, additional experiments will be necessary to determine whether there is a mechanistic link between BBB breakdown and expression of MMP‐3, MMP‐9, or the other MMPs and tissue inhibitors of metalloproteinase proteins implicated in this process .…”