Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the bloodbrain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

Preface The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, the most well known of which are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, control of cerebral blood flow, and, when barrier integrity is impaired, a contribution to the pathology of many common CNS disorders such as Alzheimer’s disease, Parkinson’s disease and stroke. Thus, many key areas of neuroscientific investigation are shared with the ‘brain barriers sciences’. However, despite this overlap there has been little crosstalk. This lack of crosstalk is of more than academic interest as our emerging understanding of the neurovascular unit (NVU), composed of local neuronal circuits, glia, pericytes and the endothelium, illustrates how the brain dynamically modulates its blood flow, metabolism, and electrophysiological regulation. A key insight is that the barriers are an essential part of the NVU and as such are influenced by all cellular elements of this unit.

Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

Increased expression of drug efflux transporters at the bloodbrain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.Up to 40% of epileptic patients respond poorly if at all to conventional pharmacotherapy, and impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure Kwan and Brodie, 2006). Seizures are known to increase the expression of drug efflux transporters at the blood-brain barrier, and recent experiments in animal models of epilepsy show that brain uptake of antiepileptic drugs can be significantly improved by coadministration of tariquidar, a selective and potent inhibitor of the ATP-driven drug efflux pump, P-glycoprotein (Brandt et al., 2006;van Vliet et al., 2006). Together, these findings point to increased P-glycoprotein expression as one consequence of seizure activity that limits pharmacotherapy with antiepileptic drugs.The present study is concerned with mechanistic links that connect seizure activity to increased P-glycoprotein expression. Our goals are to identify therapeutic targets that can be manipulated to prevent seizure-induced transporter overexpression and to improve pharmacotherapy with antiepileptic drugs. The combined in vitro/in vivo experiments are focused

Reduced clearance of amyloid-␤ (A␤) from brain partly underlies increased A␤ brain accumulation in Alzheimer's disease (AD). The mechanistic basis for this pathology is unknown, but recent evidence suggests a neurovascular component in AD etiology. We show here that the ATP-driven pump, P-glycoprotein, specifically mediates efflux transport of A␤ from mouse brain capillaries into the vascular space, thus identifying a critical component of the A␤ brain efflux mechanism. We demonstrate in a transgenic mouse model of AD [human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576 strain] that brain capillary P-glycoprotein expression and transport activity are substantially reduced compared with wild-type control mice, suggesting a mechanism by which A␤ accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16␣-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain A␤ levels compared with untreated control mice. Thus, targeting intracellular signals that up-regulate blood-brain barrier P-glycoprotein in the early stages of AD has the potential to increase A␤ clearance from the brain and reduce A␤ brain accumulation. This mechanism suggests a new therapeutic strategy in AD.A hallmark of Alzheimer's disease (AD) is the accumulation of neurotoxic amyloid-␤ (A␤) peptide within the brain. The A␤ transport-clearance hypothesis of AD proposed by Zlokovic and coworkers (Zlokovic and Frangione, 2003;Deane et al., 2004b;Zlokovic, 2005) states that reduced A␤ clearance (reduced A␤ efflux transport) from the brain underlies A␤ brain accumulation (see also Mooradian et al., 1997). This hypothesis suggests that the mechanism responsible for A␤ brain clearance itself could be a therapeutic target in AD.A␤ clearance from brain to blood has to be a two-step process. A␤ must first pass through the abluminal (brain side) and then the luminal (blood side) plasma membranes of the brain capillary endothelial cells that comprise the bloodbrain barrier. Given that A␤ is a peptide, both steps must be facilitated, involving receptors or transporters. At the abluminal membrane, the receptor low-density lipoprotein receptor-related protein 1 (LRP1) seems to be the major protein responsible for A␤ uptake from brain into capillary endothelial cells (Shibata et al., 2000; Deane et al., 2004a,b). However, the luminal membrane protein mediating the critical second step, A␤ efflux from the endothelial cells into the blood, has not been identified.One candidate is P-glycoprotein, an ATP-driven efflux transporter that under normal physiological conditions is highly expressed at the luminal membrane of the brain capillary endothelium. This transporter handles a wide spectrum of nonpolar, therapeutic drugs, some of which are small polypeptide derivatives .

The ATP-driven drug efflux pump, P-glycoprotein, is a critical and selective element of the blood-brain barrier and a primary impediment to pharmacotherapy of central nervous system (CNS) disorders. Thus, an understanding of how P-glycoprotein function is regulated has the potential to improve CNS therapy. We recently demonstrated rapid (minutes) and reversible inactivation of P-glycoprotein in rat brain capillaries signaled through tumor necrosis factor-␣ (TNF-␣) and endothelin-1 (ET-1), components of the brain's innate immune response. In this study, we examined the longer-term consequences of continuous exposure of rat brain capillaries to low levels of TNF-␣ and ET-1. Exposing brain capillaries to TNF-␣ or ET-1 caused a rapid decrease in P-glycoprotein transport activity with no change in transporter protein expression. This was followed by a 2-to 3-h plateau at the low activity level and then by a sharp increase in both transport activity and protein expression. After 6 h, transport activity and transporter protein expression was double that of control samples. TNF-␣ signaled through TNF-R1, which in turn caused ET release and action through ET A and ET B receptors, nitric-oxide synthase, protein kinase C and nuclear factor-B (NF-B) and finally increased P-glycoprotein expression and transport activity. Assuming similar effects occur in vivo, the present results imply a tightening of the selective blood-brain barrier with chronic inflammation and thus reduced efficacy of CNS-acting drugs that are P-glycoprotein substrates. Moreover, involvement of NF-B raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.

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At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET B receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-␣ (TNF-␣), activated a TNF-R1 receptor, released ET-1, activated ET B receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced Pglycoprotein activity through TNF-␣ release, ET-1 release, and ET B receptor signaling. TNF-␣ and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/ active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.