Heavy metal toxicity is a common health problem increasing globally owing to unavoidable environmental and occupational exposures [1]. Cadmium (Cd) is one of the seven most prevalent heavy metals that is linked with multiple organ toxicities. This is due to its non-biodegradable nature, long half-life, and the inevitable exposure caused by broad Cd applications in agriculture and industry [2]. Cd-related neurotoxicity is manifested by neurodegenerative changes and memory deficits that may lead to Alzheimer's disease. It may be attributed to the metal potential to pass the blood-brain barrier (BBB), depletion of the antioxidative enzymes, reactive oxygen species (ROS) generation, and neuronal apoptosis [3].

Currently, the exact mechanism by which Cd induces neurotoxic degenerative changes is not fully demonstrated, and more studies are required to establish such a debate [4]. The involvement of A Disintegrin and Metalloprotease (ADAM) family in brain injuries is still fascinating the researchers. ADAM family (proteolytic and non-proteolytic members) has vital functions in the mammalian nervous tissue. The non-proteolytic members including ADAM11, ADAM22, and ADAM23 have a crucial role in the development of nerve cells, and nerve myelination, and are related to the pathogenesis of epilepsy. Among the proteolytic ADAMs, ADAM10 and ADAM17 are best characterized due to their substrates selectivity, whose cleavage has a marvelous biological activity in the nervous system. Meanwhile, ADAM10 is essential for normal neuron development and is related to Alzheimer's disease, ADAM17 is linked to neuroinflammation, and brain injury, in addition to neurites development, outgrowth, and myelination [5].

Proteolytic ADAMs are sheddase proteases that catalyze the cleavage of the extracellular domain of integral membrane proteins, regulating their biological functions. ADAM17 (also called tumor necrosis factor-α (TNF-α) converting enzyme, TACE) is one member that promotes the cleavage of more than 80 substrates including growth factors and cytokines. TNF-α is the commonly identified cleaved cytokine to its soluble form (hence the name of TACE) followed by IL-6R, and L-selectin. ADAM17 is expressed in different organs including the brain, kidney, heart, and skeletal muscle, and its expression is variable during embryogenesis and adult life [6] [7]. Among the known membrane-tethered proteins shed by ADAM17 are the immunological cytokines (TNF-α, TGF-β, IFN-γ, IL-10, IL-4, IL-13, IL-6) and their receptors. They are major substrates, the modulation of which can trigger an inflammatory cascade [8]. Recently, ADAM10 was found to be the primary driver of angiotensin-converting enzyme (ACE) shedding in pulmonary vascular endothelium [9]; meanwhile, both ADAM10 and ADAM17 catalyze the shedding of ACE2, increasing its soluble form (sACE2) in plasma [10] [11]. However, the degree of ADAM17- or ADAM10-facilitated ACE2 cleavage is context-dependent. It may be based on organ specificity, and stimulatory conditions, or may be linked to the expression level of ADAM17 regulator iRhom2 [11].

Astrocytes are the major glial cells responsible for neuronal homeostasis within the central nervous system (CNS). Glial fibrillary acidic protein (GFAP) is a reliable marker for astrocytes and its increase is an indicator of active astrogliosis [12]. They have neuronal protective functions, particularly against heavy metal toxicity; however, they are vulnerable and main targets for heavy metal neurotoxicity. Astrocytes contribute to antioxidative functions, synapse development and maturation, glutamate uptake, and energy metabolism [13] [14]. Based on the findings of a recent in vitro study [15], ADAM17 was reported to be involved in astrocyte activation. The study revealed ADAM17 upregulation in stimulated HEB astrocyte cell lines, and ADAM17 inhibition suppressed the induced astrocytes' inflammatory response.

ACE2 is a critical enzyme in the renin-angiotensin system (RAS), that degrades the vasoconstrictor angiotensin II (Ang-II) into the vasodilator Ang-(1–7) in many tissues like the heart, blood vessels, kidney, and brain tissues. So, ACE2 could counterbalance the vasoconstrictor and proliferative activities of Ang-II by increasing the vasodilatory and anti-proliferative functions of Ang-(1–7). Hence, the ACE2/Ang-(1–7) pathway has major opposing effects against many pathological processes (such as oxidative stress, inflammation, and neurodegeneration) produced by Ang II and its receptor (AT1R). So, any alterations in ACE2 expression and or activity might be involved in several cardiac, vascular, and neurodegenerative diseases [16].

In the current experiment, the authors examined the possible involvement of ADAM17 activation and ACE2 shedding in Cd-induced brain injury and neuroinflammation. Also, ADAM17 suppression was attempted to highlight the anticipated protective function against Cd neurotoxicity. ADAM17 was investigated herein as it has the designated function of dampening the inflammatory cytokine signaling in the brain, rather than ADAM10, as declared by Pruessmeyer and Ludwig [17].