Despite the advances in our knowledge of the complex pathophysiology of TBI, it remains one of the leading causes of morbidity and mortality globally. According to the Centers for Disease Control and Prevention (CDC, USA), there were approximately 223,135 TBI-related hospitalizations in 2019 and 64,362 TBI-related deaths in 2020. More than 611 TBI-related hospitalizations and 176 TBI-related deaths per day, thus making it a significant cause of morbidity and mortality.

Cerebral edema following TBI plays a critical role in the high mortality and morbidity rates associated with TBI. In addition to its mechanical impact on the brain, raised ICP, impaired cerebral perfusion and oxygenation, and cerebral edema contribute to further brain ischemic injuries. This cerebral edema can occur either due to the disruption of the BBB resulting in extracellular fluid accumulation, causing "vasogenic" edema, or due to sustained intracellular fluid accumulation causing "cytotoxic/cellular" edema (Unterberg et al., 2004; Alluri et al., 2016). Despite the predominance of cytotoxic (or cellular) edema in the first week after TBI, a significant rise in intracranial tension can occur only with the addition of fluid to the cranial vault from the vasculature. Hence, regulation of BBB hyperpermeability has become a focus of recent research seeking to manage post-traumatic cerebral edema and associated pathologies.

One of the first contributing factors to BBB breakdown in TBI is believed to be due to the immediate mechanical disruption by the contusion edema generated due to osmotic potential across the high osmolar central necrotic tissue and surrounding brain tissue (Jha et al., 2019). However, this mechanical disruption, although the most immediate cause, is not the sole and significant etiology of BBB breakdown (Jha et al., 2019). Recent evidence demonstrates that many other factors like proinflammatory cytokines, chemokines, Vascular Endothelial Growth Factor A, Matrix metalloproteinases (MMPs), and Substance P also contribute to the development of cerebral edema following traumatic brain injury.

Matrix metalloproteinases (MMPs) form a multigene family of zinc-dependent endopeptidases that are primarily secreted and act outside the cells (Chaturvedi and Kaczmarek, 2014). Four main classes have been found—collagenases, stromelysins, gelatinases, and membrane-bound MMPs. They are initially synthesized as inactive zymogens and negligibly expressed in normal conditions and are activated through the proteolytic removal of a cysteine–zinc interaction (de Almeida et al., 2022). Matrix Metalloproteinases play a critical role in the central nervous system (CNS) via breakdown of the BBB, demyelination, axonal injury, and activation of inflammation via tumor necrosis factor-alpha (TNF-α) and macrophages. As a result, MMPs impact CNS pathology through neurogenesis, angiogenesis, apoptosis, and inflammatory modulation (Chang et al., 2014)

In a TBI, oxidative stress, proinflammatory cytokines, chemokines, infiltrating or resident inflammatory cells, injured neurons, and endothelial cells can activate MMPs. Among the various MMPs, MMP-2 and MMP-9 are the most abundantly expressed and extensively studied in the CNS regarding their impact on BBB integrity. MMP-2 is a gelatinase tethered to the cell surface, thus having a very restricted proteolytic reach. Meanwhile, MMP-9 is released into the extracellular space and can have effects distant from the release site. Even though neutrophils are the primary source of MMP-9, it is also expressed in other invading leukocytes, endothelial cells, and sometimes weakly in astrocytes (Jha et al., 2019).

Activation of MMP-9 leads to the digestion of collagen type IV, laminin, and fibronectin—significant components of the basal lamina surrounding cerebral blood vessels, and breakdown the inter-endothelial tight junction proteins. In addition, the MMP-9 promoter region contains activator protein-1and nuclear factor-kB, both of which respond to inflammatory stimuli and specifically attack the basal lamina through the fibronectin-binding domain (Chang et al., 2014). Thus, targeting MMP-9 has the potential to regulate secondary injuries following TBI via providing protection to the neurovascular systems.

The primary goal of this article is to evaluate the pharmacological management of edema following TBI by reviewing the literature on various endogenous or exogenous compounds acting on MMP-9, either directly or indirectly inhibiting its functions.

The activation of MMP-9 enzyme has been linked to disruption of the BBB in individuals with traumatic brain injury (TBI). This process is thought to be a major factor in neurovascular dysfunctions and neurodegenerative conditions associated with TBI. Following inflammation, MMP-9 is secreted in a proenzyme form into the extracellular matrix (Rosenberg, 1995). As mentioned above, it has a role in secondary injury following various brain injuries and is associated with destruction of extracellular matrix and basal lamina and inter endothelial tight and adherens junctions via targeting tight/adherens junction proteins. Also, a positive correlation between serum MMP-9 levels and radiological evidence of BBB destruction suggests the significant role played by MMP-9 in the breakdown of the basal lamina. Plasminogen activators and MMPs act in a cascade to destroy the extracellular matrix (Rosenberg, 1995), and MMP-9 has been attributed to post-traumatic epilepsy. Unfortunately, to date, the role of MMP-9 in post-traumatic epilepsy (PTE) evoked by TBI has not been clearly known. However, various studies in animal models with genetic modifications of MMP-9 (MMP-9 knockout mice that had no functional MMP-9 and mice with MMP-9 overexpression in the brain) concluded that mice with deficient MMP-9 had smaller post-TBI cortical lesion volumes, whereas MMP-9 overexpression in mice had more significant lesion volumes [the occurrence of PTE was correlated with the size of the lesion after injury] in the cerebral cortex (Pijet et al., 2018).

As various functional molecules have been confirmed to induce BBB disruption, drugs targeted to these factors are expected to have anti-edema effects. In experimental animals, MMP-9 inhibitors have been shown to reduce cerebral edema. In addition, the administration of GM6001, a broad-spectrum MMP inhibitor, reduced injury volume and brain water contents after intracerebral hemorrhage in mice. Similar observations were made after TBI in rats. Moreover, other broad-spectrum MMP inhibitors, such as BB-1101 and MMI270, also reduced BBB hyperpermeability and brain edema in experimental animals with cerebral ischemia, and cold injury. These results suggest that MMP inhibitors are prime drug candidates for vasogenic edema (Michinaga and Koyama, 2015).

In this review article, we have identified multiple endogenous or exogenous MMP-9 inhibitors already in pre-clinical and/or clinical studies in TBI and/or non-TBI-related conditions based on recent literature. Although we have identified and included several significant drug candidates based on their cellular, molecular, pathobiological and their potential significance in pre-clinical and clinical studies, we may have missed several of them with potential benefits. For the ease of understanding, we have included the various MMP-9 inhibitors under the categories, ‘primary MMP-9 inhibitors’ and ‘other drugs with MMP-9 inhibitory properties. Additionally, a table that describes all the listed drugs and their biological action as well as a schematic diagram (Fig. 1) showing the effect and interactions of each of the listed drugs have been included.