Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator

Abstract

Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy. When neuronal activity is stimulated in the adult rat and mouse hippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is transcriptionally induced. The activity of tPA in neural tissue is correlated with neurite outgrowth, regeneration and migration, suggesting that it might be involved in neuronal plasticity. Here we show that tPA is produced primarily by microglia in the hippocampus. Using excitotoxins to induce neuronal cell loss, we demonstrate that tPA-deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild-type mice. These findings identify a role for tPA in neuronal degeneration and seizure.

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice

“…As reported previously, wild-type but not tPA -/-mice exhibit neurodegeneration in the hippocampus after intrahippocampal KA injection (Fig. 1D, top row; compare loss of Cresyl-Violet-staining pyramidal neurons in CA1-3 regions on the injected side of the wild-type mouse with the comparable regions on the non-injected side of the wildtype mouse and with the injected side in the tPA -/-mouse) (Tsirka et al, 1995). We now show that the extent of degeneration observed colocalizes with the region where nTyr formation is detected (Fig.…”

“…For intrahippocampal injections, adult mice were injected as described earlier (Tsirka et al, 1995;Tsirka et al, 1996) with 0.9 nmol kainate (KA; Sigma), unless otherwise stated. Mice were sacrificed at the indicated times after injection, and brains were removed, frozen and sectioned.…”

“…tPA also functions in the central nervous system (CNS) by mediating excitotoxicity in the hippocampus (Tsirka et al, 1995). Mice deficient in tPA are resistant to the excitotoxic neuronal cell death that normally follows intrahippocampal injection of kainate (KA), and this resistance reflects a role for tPA in cell death acutely, rather than it being the result of altered brain development in the absence of tPA (Tsirka et al, 1995;Tsirka et al, 1996).…”

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

“…PAI-1 was also reported to rescue neurons from kainate-induced death in both wild-type and tPA-/-mice (Tsirka et al, 1996). Additionally, tPA has also been shown to exacerbate neuronal damage in tPA-deficient mice after excitotoxic insult (Tsirka et al, 1995) or focal cerebral ischemia in mice (Wang et al, 1998). Of interest, a recent report demonstrates that tPA in the amygdala is critical for stress-induced neuronal remodeling and the development of anxiety-like behavior, and is subsequently inhibited by PAI-1 .…”

“…Smad3/4 has a prominent role in regulating the expression of proteins involved in neuronal survival/death, differentiation, and plasticity (reviewed in Sanyal et al, 2004;Gomes et al, 2005). One of the Smad3/4-regulated protein targets is plasminogen activator inhibitor type-1 (PAI-1, also referred to as Serp1), which binds and inactivates tissue-type plasminogen activator (tPA), a multifaceted protein implicated in neurite outgrowth (Krystosek and Seeds, 1981), neuronal migration (Moonen et al, 1982;Seeds et al, 1999), learning (Qian et al, 1993;Seeds et al, 1995), excitotoxicity (Tsirka et al, 1995), synaptic plasticity (Baranes et al, 1998;Fiumelli et al, 1999;Neuhoff et al, 1999), stress response , and pathogenesis of mood disorders (Eskandari et al, 2005;Tsai, 2006). Using small interfering RNA (siRNA) and dominant negative mutants specific to GSK-3α and GSK-3β, we recently reported that GSK-3α inhibition causes an upregulation of Smad3/4-dependent transactivation and PAI-1 protein levels, while inhibition of GSK-3β induces a downregulation of Smad3/4 transactivation and PAI-1 expression (Liang and Chuang, 2006).…”