Introduction: Recombinant human tissue plasminogen activator (tPA) has been used mainly as a thrombolytic agent for the treatment of acute ischemic stroke. However, it has also been shown to promote neuroplasticity in studies of ischemia in animals. The present study was designed to investigate the beneficial effects of treating traumatic brain injury (TBI) with tPA in rats.
Methods: Adult male Wistar rats were subjected to controlled cortical impact (CCI) and then treated intranasally with saline or tPA (n=8/group). An additional group of rats was subjected to sham surgery and treated with tPA. tPA at a dose of 600 µg/rat was administered intranasally at Days 7 and 14 post TBI. Neurological functional measurements were performed using Morris water maze test (MWM), neurological severity scores (NSS), and foot fault test. An anterograde neuronal tracer, biotinylated dextran amine, was injected into the contralesional sensorimotor cortex to study axonal sprouting into the denervated side of the cervical spinal cord. Brain-derived neurotrophic factor (BDNF) expression was studied with immunostaining and Western blot analysis. tPA content in the brain was assessed with ELISA assay, and tPA activity was measured with amidolytic and zymography assays.
Results: Intranasal administration of tPA significantly increased tPA protein level (ELISA) and tPA activity in brain extracts after TBI (amidolytic and zymography assays, p<0.05). tPA treatment improved cognitive (MWM) and sensorimotor functional recovery (NSS and foot fault tests) in rats after TBI (p<0.05). tPA enhanced neurogenesis in the dentate gyrus and promoted axonal sprouting of the corticospinal tract originating from the contralesional cortex into the denervated side of the cervical spinal cord. In addition, tPA increased the level of BDNF (p<0.05).
Conclusions: Intranasal tPA treatment improves functional recovery and promotes brain neurogenesis and spinal cord axonal sprouting after TBI, which may be mediated partially by tPA/plasmin-dependent maturation of BDNF.
Patient Care: This study adds to our growing body of knowledge on the beneficial effects of tPA after neural injury which can be tried clinically as a potential treatment for TBI.
Learning Objectives: By the conclusion of the session participants should be able to:
1) Describe the beneficial effects of tPA treatment on improving functional outcome after TBI.
2) Identify that tPA treatment promotes neurogenesis in brain and enhances axonal sprouting in the spinal cord after TBI
3) Identify that a simple mode of delivery, i.e., intranasal administration of tPA, has significant beneficial effects on outcome after TBI