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Published on: February 28, 2021
Myeloperoxidase Nuclear Imaging for Epileptogenesis
Yinian Zhang1, Daniel P Seeburg1, Benjamin Pulli1
1From the Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China (Y.Z., Y.P.); Center for Systems Biology and Department of Radiology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114 (Y.Z., D.P.S., B.P., G.R.W., L.B., W.A., S.S., Y.I., M.A., E.R., A.M., E.J.K., C.W., F.K.S., J.W.C.); and Department of Neurosurgery, Massachusetts General Hospital, Boston, Mass (W.Z.).
Purpose:
To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis.
Materials And Methods:
The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05.
Results:
MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology.
Conclusion:
The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.
Insights
Myeloperoxidase (MPO) plays a key role in epilepsy development. Inhibiting MPO can delay seizures and reduce their severity, suggesting MPO is a potential therapeutic target and imaging biomarker for epilepsy.
Area of Science:
- Neuroscience
- Immunology
- Medical Imaging
Background:
- Epileptogenesis, the process by which epilepsy develops, involves complex biological mechanisms.
- Inflammation is increasingly recognized as a contributing factor in the progression of epilepsy.
- Myeloperoxidase (MPO) is an enzyme associated with inflammatory processes.
Purpose of the Study:
- To investigate the role of myeloperoxidase (MPO) in the development of epilepsy (epileptogenesis).
- To evaluate the potential of molecular nuclear imaging for noninvasively mapping brain inflammation in epilepsy.
Main Methods:
- Studies were conducted on pilocarpine-induced epileptic mice treated with an MPO inhibitor or saline.
- In vivo imaging of brain MPO activity was performed using single photon emission computed tomography/computed tomography (SPECT/CT) with Indium-111-labeled tracer.
- Assessment of MPO's role in spontaneous recurrent seizures included clinical, biochemical, and histopathological analyses.
- Human epilepsy and non-epilepsy brain tissue samples were stained for MPO expression.
Main Results:
- MPO and leukocyte levels were elevated in the brains of epileptic mice.
- Inhibition of MPO significantly delayed the onset and reduced the severity of spontaneous recurrent seizures.
- MPO inhibition also decreased mossy fiber sprouting and matrix metalloproteinase activity, indicating MPO acts upstream of these factors.
- In vivo imaging successfully mapped MPO activity in the hippocampus during epileptogenesis.
- Human epilepsy tissue showed positive MPO immunostaining, unlike control tissue.
Conclusions:
- Myeloperoxidase (MPO) is critically involved in epileptogenesis.
- MPO represents a promising therapeutic target for epilepsy treatment.
- MPO can serve as a valuable imaging biomarker for epilepsy, with potential for clinical translation.
