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Unveiling Lovastatin's Anti-Inflammatory Potential in Mouse's Brain during Acute Trypanosoma cruzi Infection
Beatriz Matheus de Souza Gonzaga1, Líndice Mitie Nisimura1, Laura Lacerda Coelho1
1Laboratório de Inovações Em Terapias, Ensino E Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, RJ, Brazil.
Insights
Lovastatin did not improve brain microcirculation in experimental Chagas disease (CD). However, this statin showed anti-inflammatory effects by reducing certain immune cells and markers in the brain during acute infection.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chagas disease (CD) can cause neurological complications like meningoencephalitis and stroke, often linked to cerebral microvasculopathy.
- Current CD treatments (benznidazole, nifurtimox) have limited chronic phase efficacy and significant side effects, necessitating new therapeutic strategies.
- Statins, like lovastatin, possess pleiotropic effects including anti-inflammatory and endothelial-protective properties, suggesting potential for treating CD-related brain issues.
Purpose of the Study:
- To investigate the therapeutic potential of lovastatin (LOV) in mitigating brain microvasculopathy and inflammation during acute Chagas disease (CD) infection.
- To evaluate LOV's impact on cerebral microcirculation, immune cell infiltration, and inflammatory markers in a mouse model of experimental CD.
- To determine if LOV exhibits trypanocidal activity or affects parasite load in the context of acute infection.
Main Methods:
- Swiss Webster mice were infected with the Y strain of *Trypanosoma cruzi*.
- Lovastatin (20 mg/kg/day) was administered intraperitoneally for 14 days, starting 24 hours post-infection.
- Analysis included parasitemia, cerebral blood flow, capillary density, leukocyte-endothelial interactions, and brain expression of inflammatory markers (CD3+, F4/80+, eNOS, VCAM-1, MCP-1, ICAM-1).
Main Results:
- Lovastatin treatment did not alter parasitemia, cerebral microcirculation, or reduce cerebral blood flow in *T. cruzi*-infected mice.
- LOV did not prevent increased CD3+ T-cells or eNOS levels in the infected brain.
- LOV administration prevented the increase in F4/80+ macrophages and ICAM-1 levels, suggesting an anti-inflammatory effect, while VCAM-1 and MCP-1 remained unchanged.
Conclusions:
- Lovastatin does not appear to directly improve cerebral microcirculation or reduce parasite load in acute experimental Chagas disease.
- LOV demonstrated a partial anti-inflammatory effect by modulating specific immune cell populations and adhesion molecules in the infected brain.
- Further research is required to fully elucidate the role and potential benefits of lovastatin in managing neurological complications of Chagas disease.
Abstract:
Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental Trypanossoma cruzi acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of T. cruzi. Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by T. cruzi infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the T. cruzi-infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi. These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection.
