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.

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 .