In the brain, all physiological and pathological events are characterized by a continuous interplay among neurons, extracellular environment, and glial cells. This multifunctional cell population tightly controls the complex brain homeostasis being determinant in shaping both neuron physiology and the outcome of neural disorders.

Neurons and glia communicate through secreted factors (e.g., chemokines, cytokines, growth factors), undergoing modifications in shape, (post)transcriptional properties, and physiology. Most of these events imply remodeling of the extracellular matrix (ECM) and of its link with a number of cell surface receptors and adhesion molecules.

In particular, microglia (MG), the brain innate immune system, rules out important aspects of neuronal response to injuries by transforming into diversified reactive states. In pathological conditions, glial cell activation ignites brain inflammatory processes, which appear to be part of a common immunological pathway in clinically heterogeneous diseases.

MG transition from a ¿surveillance¿ to an active state is controlled by multiple extracellular signals acting through a multitude of receptors, yet to be fully identified. Although a protective role of neuroinflammation in some neurodegenerative paradigms has been reported, several evidences also suggest that it may contribute in enhancing and accelerating neuronal death.

Among secreted factors, extracellular proteases, as metalloproteinases (MMPs), may play fundamental roles in the development of brain inflammatory events. This is a large family of endopeptidases synthesized, at various levels and with different patterns, by all brain cell types.

Collectively, MMPs can cleave all ECM proteins and several other substrates, including chemokines, growth factors, cell surface receptors, and adhesion molecules. Synthesized as inactive zymogens, they can be primed by other proteases, and their activity is tightly regulated by tissue-inhibitors of metalloproteinases (TIMPs). In brain, MMPs are expressed at low levels and are promptly up-regulated in various physiological and pathological conditions.

Noteworthy, MMPs and TIMPs have been shown to regulate cytokine and free radical production in MG in autocrine/paracrine manner and, vice versa, cytokines appear to be potent regulators of MMPs production by MG and astrocytes.

As a reflection of their complex regulation, MMPs have been suggested to play deleterious roles in the acute phase of inflammation (e.g., after stroke), contributing to blood-brain barrier disruption and cell death, but also to mediate tissue repair and neurovascular remodeling at later stages, favoring neuronal functional recovery.

Previous results obtained by the applicant together with the host laboratory have shown an increase in mRNA and protein levels, as well as activity, of MMP-9 (a MMP highly expressed in brain), after parkinsonism induced by acute administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This is concomitant with a significant loss of the dopaminergic neurons of the substantia nigra and activation of MG, astrocytes, and oligodendrocytes.

The main cell type expressing MMP-9 are neurons, but after MPTP intoxication also reactive MG and oligodendrocytes express it to some extent. The part of the project that will be developed in the host laboratory aims at increasing our knowledge on the role of MMP-9 in the development of neuroinflammation and neuronal degeneration/regeneration.

This will be achieved by in vivo administration, in MPTP-treated mice, of MMP-9 inhibitors, to investigate whether blocking MMP activity enhances or reduces the inflammatory response and, ultimately, dopaminergic neuron death. Full exploration of this issue is important in view of therapeutic perspectives in which the use of selective inhibitors/enhancers of specific MMPs and TIMPs, administered in the opportune time window, could contribute to the treatment of different brain pathologies.