Nandrolone Abuse Prior to Head Trauma Mitigates Endoplasmic Reticulum Stress, Mitochondrial Bioenergetic Deficits, and Markers of Neurodegeneration

• Published in: Molecular neurobiology Vol. 62; no. 6; pp. 6951 - 6967
• Main Authors: Rodolphi, Marcelo S., Strogulski, Nathan R., Kopczynski, Afonso, Sartor, Monia, Soares, Gabriela, de Oliveira, Vitoria G., Vinade, Lucia, Dal-Belo, Chariston, Portela, Juliana V., Geller, Cesar A., De Bastiani, Marco A., Justus, Jijo S., Portela, Luiz Osorio C., Smith, Douglas H., Portela, Luis V.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2025; Springer Nature B.V
• Subjects: Abuse; Aggressive behavior; Amyloid precursor protein; Animals; Apoptosis; Bioenergetics; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Calcium (mitochondrial); Calcium efflux; Cell Biology; Craniocerebral Trauma - complications; Craniocerebral Trauma - metabolism; Craniocerebral Trauma - pathology; Endoplasmic reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress - drug effects; Energy Metabolism - drug effects; Heat shock proteins; Hydrogen peroxide; Male; Membrane potential; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurobiology; Neurodegeneration; Neurology; Neurosciences; Oxygen consumption; Principal components analysis; Protein folding; Spatial memory; Steroid hormones; Tau protein; Taurochenodeoxycholic Acid; Traumatic brain injury; β-Amyloid; Abuse; Nandrolone; Traumatic brain injury
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-024-04488-8

The abuse of synthetic steroids, such as nandrolone decanoate (ND), is often associated with violent behavior, increasing the risk of traumatic brain injury (TBI). After a TBI, proteins like APP, β-amyloid peptide-42 (Aβ42), and phosphorylated tau (pTau) accumulate and trigger endoplasmic reticulum (ER) stress associated with an unfolded protein response (UPR). The involvement of mitochondrial bioenergetics in this context remains unexplored. We interrogate whether the abuse of ND before TBI alters the responses of ER stress and mitochondrial bioenergetics in connection with neurodegeneration and memory processing in mice. Male CF1 adult mice were administered ND (15 mg/kg) or vehicle (VEH) s.c. for 19 days, coinciding with the peak day of aggressive behavior, and then underwent cortical controlled impact (CCI) or sham surgery. Spatial memory was assessed through the Morris water maze task (MWM) post-TBI. In synaptosome preparations, i) we challenged mitochondrial complexes (I, II, and V) in a respirometry assay, employing metabolic substrates, an uncoupler, and inhibitors; and ii) assessed molecular biomarkers through Western blot. TBI significantly increased APP, Aβ42, and pTau Ser396 levels, along with ER-stress proteins, GRP78, ATF6, and CHOP, implying it primed apoptotic signaling. Concurrently, TBI reduced mitochondrial Ca 2+ efflux in exchange with Na + , disturbed the formation/dissipation of membrane potential, increased H 2 O 2 production, decreased biogenesis (PGC-1⍺ and TOM20), and ATP biosynthesis coupled with oxygen consumption. Unexpectedly, ND abuse before TBI attenuated the elevations in APP, Aβ42, and pTau Ser396 , accompanied by a decrease in GRP78, ATF6, and CHOP levels, and partial normalization of mitochondrial-related endpoints. A principal component analysis revealed a key hierarchical signature featuring mitochondrial Ca 2+ efflux, CHOP, GRP78, TOM20, H 2 O 2 , and bioenergetic efficiency as a unique variable (PC1) able to explain the memory deficits caused by TBI, as well as the preservation of memory fitness induced by prior ND abuse.