Bowman–Birk inhibitor suppresses autoimmune inflammation and neuronal loss in a mouse model of multiple sclerosis

Abstract

The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor. BBI concentrate (BBIC) is an extract enriched with BBI, but predominantly contains other ingredients including several protease inhibitors. We previously found that BBIC administration to Lewis rats with experimental autoimmune encephalomyelitis (EAE) significantly suppresses disease. In the present study we determined whether BBI mediates the suppressive effects of BBIC in EAE, evaluated its potential neuroprotective effects, and investigated mechanisms of BBI action. We tested effects of purified BBI on clinical and histopathological parameters of EAE in two models (relapsing/remitting EAE in SJL/J mice and chronic EAE in C57BL/6 mice). Effects of BBI were compared to BBIC in relapsing/remitting EAE, and effects of BBI on neuronal survival were examined during acute optic neuritis. Treatment with BBI in both EAE models significantly improved EAE disease parameters (onset, severity, weight loss, inflammation and demyelination). BBI significantly reduced the incidence of optic neuritis and prevented loss of retinal ganglion cells. In most experiments proliferation of immune cells derived from BBI-treated mice was significantly lower relative to control groups. Using Boyden's chamber assay we found that BBI inhibited invasiveness of activated splenocytes through the matrigel barrier. BBI also induced higher production of EAE-suppressive cytokine IL-10 by immune cells. These results demonstrate that BBI is the active component of BBIC that ameliorates clinical EAE. BBI reduces inflammation and attenuates neuronal loss, making it an excellent candidate for oral therapy in MS. BBI likely ameliorates EAE by inhibiting multiple pathways involved in disease pathogenesis.

Role of serine proteases in inflammation: Bowman–Birk protease inhibitor (BBI) as a potential therapy for autoimmune diseases

“…As we expected, BBI attenuated clinical disease scores more efficiently than BBIC (Touil et al, 2008). Furthermore, oral BBI therapy also decreased inflammation and demyelination in the spinal cord of treated animals.…”

Detecção de inibidores de proteases em sementes de Punica granatum

“…O inibidor do tipo BBI, que apresenta banda característica entre 10 e 17 kDa e com picos de tempo de retenção aos 12 e 13 minutos no HPLC, é descrito como um potente redutor da atividade da tripsina, 9 sugerindo que o produto obtido no extrato enriquecido das sementes de P. granatum seja do tipo BBI. Novos estudos devem ser realizados para a caracterização dos picos com tempo de retenção em 28 e 40 min encontrados no HPLC.…”

“…8 Pesquisas têm demonstrado a utilização de inibidores de proteases no tratamento de enfermidades devido suas funções de regulação de diferentes processos em que as proteases estão envolvidas, que englobam a quebra de proteínas intracelulares, transcrição, ciclo celular, invasão celular e apoptose, através da degradação seletiva de substratos alvo. 4,9 A Punica granatum é árvore de pequeno porte oriunda da África boreal, facilmente cultivada nas regiões quentes e temperadas do mundo inteiro, que pertence à família Lythraceae (antiga Punicaceae) e apresenta taninos, alcaloides, amido, ácido gálico, vitaminas B2, C e D, magnésio e ferro em seus constituintes. 10 Apesar dos inibidores de proteases serem tradicionalmente encontrados em leguminosas, a P. granatum foi selecionada para se avaliar a capacidade de obtenção de inibidores de proteases, nunca encontrados nas sementes dessa espécie vegetal, visto a sua utilização na medicina tradicional.…”

Bowman-Birk Inhibitors from Legumes: Utilisation in Disease Prevention and Therapy

“…The search for novel therapeutic agents that can be administered orally, and act synergistically with existing therapies, would be useful for patients with MS. Purified soybean BBI and BBIC have been shown to be effective in the suppression of experimental autoimmune encephalomyelitis in rodents, a model to study the pathogenic mechanisms of MS and to test potential therapies [92]. The oral administration of BBI in mice caused an improvement of several disease parameters (onset, severity, weight loss, inflammation, neuronal loss and demyelination), with no apparent adverse effects [93,94]. Interestingly, BBI ameliorated disease, even when treatment was initiated after disease onset, via an IL-10-dependent mechanism [94]; the molecular basis for the induction of IL-10 production by BBI remains to be elucidated.…”

“…The oral administration of BBI in mice caused an improvement of several disease parameters (onset, severity, weight loss, inflammation, neuronal loss and demyelination), with no apparent adverse effects [93,94]. Interestingly, BBI ameliorated disease, even when treatment was initiated after disease onset, via an IL-10-dependent mechanism [94]; the molecular basis for the induction of IL-10 production by BBI remains to be elucidated. Recent studies have demonstrated that BBI is responsible for delayed onset of disease but did not stop disease development, which became similarly severe in treated mice as in control animals [95,96].…”