Ameliorating Effects of Adalimumab on Rabbits with Experimental Cerebral Vasospasm After Subarachnoid Hemorrhage

Abstract

BACKGROUND: Adalimumab (ADA), which is a new-generation recombinant human monoclonal antibody for tumor necrosis factor α (TNFα), has strong anti-inflammatory effects. The role of enhanced inflammation is well established for the development and progression of cerebral vasospasm. Investigated in the present study is the probable ameliorating and neuroprotective effects of ADA in rabbits using a cerebral vasospasm model with biochemical and histopathological methods. METHODS: Thirty male New-Zealand white rabbits were randomly divided into control, subarachnoid hemorrhage (SAH) only and SAH plus ADA treatment groups. SAH was established as a single cisterna magna autologous arterial blood injection. ADA treatment was started just after intracisternal blood injection and continued for 72 hours once a day. The animals were sacrificed 72 hours after the induction of SAH, serum and brainstem tissue obtained for investigations. RESULTS: Brainstem tissue and plasma levels of tumor necrosis factor-alpha and Interleukin-1β, brainstem tissue Matrix metalloproteinase-9 levels increased after SAH and partly decreased after treatment. Plasma levels of brain-derived neurotrophic factor decreased after SAH and partly restored after treatment. ADA treatment significantly increased the mean cross-sectional area of the vasospastic basilar arteries, reduced the basilar artery wall thickness and also ameliorates enhanced endothelial apoptosis. CONCLUSION: Findings obtained in this study suggest that ADA is an effective neuroprotective agent for ameliorating cerebral vasospasm in experimental rabbit vasospasm.

Systemic Inflammation after Aneurysmal Subarachnoid Hemorrhage

“…It also mediates inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis [ 177 , 178 ]. TNF-α is found to be elevated in the brain parenchyma, serum, and CSF 2–10 days after aSAH [ 156 , 179 , 180 , 181 , 182 ]. It causes neuron apoptosis [ 183 ] and BBB disruption [ 184 ] in in vivo brain injury models.…”

“…TNF-α inhibition has shown improved outcomes in treating patients with rheumatoid arthritis, psoriasis, and inflammatory bowel disease [ 295 , 296 ]. Results from a rabbit aSAH model indicate that adalimumab, an anti-TNF-α monoclonal antibody, helps to inhibit cerebral vasospasm [ 179 ]. The results show that plasma TNF-α (23.23 ± 1.29 vs. 44.86 ± 2.58 pg/mL, p < 0.05) and IL-1β (50.05 ± 2.21 vs. 55.00 ± 3.92 pg/mL) levels decreased significantly, as did brain parenchyma MMP-9 expression (0.85 ± 0.09 vs. 1.29 ± 0.20 ng/mg protein, p < 0.05).…”

Prevention and treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage

“…Monoclonal antibodies have been explored for the treatment of PHCV. Specifically, adalimumab, a monoclonal antibody blocking TNF-α significantly increased the cross-sectional area of basilar arteries, reduced basilar artery wall thickness, and reduced endothelial apoptosis in rabbits with PHCV [98]. Blocking VEGF signaling with bevacizumab improved cerebral vasospasm and neurocognitive functioning following SAH in rabbits [99].…”

Clinical Potential of Immunotherapies in Subarachnoid Hemorrhage Treatment: Mechanistic Dissection of Innate and Adaptive Immune Responses

“…Adalimumab (ADA), a recombinant human IgG1 monoclonal antibody targeting TNF-α, prevents the binding between TNF-α and its receptor [ 191 ]. According to a series of experimental studies, administration of ADA markedly enlarges the mean cross-sectional area of the vasospastic basilar arteries (BA), decreases the arterial wall thickness, and ameliorates endothelial apoptosis [ 229 ].…”