Copper depletion ameliorates neuronal damage after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a severe subtype of stroke. There are currently no specific treatment strategies for secondary brain injury and neurological deficits following ICH. Copper (Cu) is an essential cofactor for all living organisms. Cytotoxicity can occur when copper ion concentration exceeds the homeostatic threshold, leading to cell death. However, the relationship between copper and ICH is unclear.

In vivo, an ICH model was established in male Sprague-Dawley rats by stereotactically injecting autologous blood into the right basal ganglia. In vitro, we employed hemin and CuCl₂ to simulate ICH conditions and induce cuproptosis in BV2 microglial cells. To investigate the role of copper in brain injury and neuronal damage, we administered the copper chelator tetrathiomolybdate (TTM) and knocked down the essential cuproptosis gene ferredoxin 1 (FDX1).

Our findings demonstrate that following ICH, elevated copper levels and FDX1 expression, low expression of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and lipoic acid synthetase (LIAS), loss of mitochondrial membrane potential and neuronal impairment (increased growth associated protein 43 (GAP43) and decreased microtubule associated protein 2 (MAP2) expression), ultimately lead to neuronal death. Both TTM and si-FDX1 treatment attenuated the copper overload and inhibited cuproptosis, thereby ameliorating the ICH-induced phenotype.

Copper depletion attenuates ICH-induced neuronal damage by inhibiting cuproptosis, highlighting a potential therapeutic strategy for mitigating secondary brain injury and neuronal damage following ICH.