Neurocognitive Protection by Statins in Cerebral Malaria

7/30/2019 Neurocognitive Protection by Statins in Cerebral Malaria

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Neurocognitive Protection By Statins InCerebral Malaria


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INTRODUCTION

The burden of malaria is enormous with more than 40%of the

worlds population at risk for infections caused byPlasmodium

Parasites.

P. falciparum is the principal cause of syndromes of

severe malaria, including cerebral malaria, which involves

neurological and systemic manifestations and in which

coma is the defining feature.Approximately, 5 lakhs to 8 lakhs children developcerebral malaria each year in Africa alone.

The mortatlity rate is around 20-25%.


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The mice were infected with Plasmodium bergheiANAK(PbA).

These models provided important insights intopathogenesis of cognitive dysfunction with cerebralmalaria.

In cerebral malaria, exacerbated inflammatory responseare the major cause for organ dysfunction.

Other complications are pro-inflammatory cytokines andchemokines activate leukocytes and endothelial cells and

leads to microvascular plugging, impaired blood flow,breakdown of blood-brain barrier, local neuroinflammationand apoptosis.

Statins can modify two processes: neuroinflammation and

activation of proinflammatory microglia.


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METHOD

Uncloned Plasmodium bergheiANAK (PbA) were used.

Mice red blood cells were infected with PbA strain.

On day 3 and day 6, parasitemia and neurobehavourial

signs of CM were monitored. Animals positive for CM were identified by signs such as

curved trunk, skin colour alterations, heart rate,decreased grip strength, limb, abdominal and body toneand body temperature alterations.

Animals that were positive for CM were immediatelystarted on oral chloroquine treatment, Lovastatin or bothand were treated for 7 days.


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RESULTS

Animals treated with lovastatin alone, did not show anyanti-parasitic effect.

Lovastatin treatment did not prevent mortality when givenalone despite slight delayed effect.

Animals treated with chloroquine treatment were rescuedbut lacked contextual memory.

In contrast, animals treated with lovastatin in addition tochloroquine showed a significant reduction in the number

of crossings and rearing sessions, indicating intactcontextual memory.


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In order to investigate potential mechanism of theneuroprotective effect of statins in experimental CM, theyanalyzed the influence of lovastatin on neuroinflammatory

parameters. Animals that showed clear signs of CM were done

intravital microscopic examination of the pial microvesselsthrough cranial window.

There was a marked decrease in functional capillarydensity and adhesion of leukocytes increased.

But this was reversed in animals treated with lovastatin.


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Representative images offluorescence intravitalmicroscopy of pial vessels ofuninfected mice (A and B)infected mice (C and D).

Venules with adherent androlling Rhodamine-labeledleukocytes inuninfected mice (E and F)infected mice (G and H)


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BBB disruption is a common consequence of CM.

Evans blue dye was used as a marker to observeincreased vascular permeability.

PbA infected mice that were positive for clinical signs ofCM, showed increased in BBB permeability.

Animals on lovastatin treatment showed significantdecrease in BBB disruption.

The beneficial effect was most for 20mg/kg (around 48%inhibition)


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Brain histology was examinedusing tissue from the followinggroups of animals:uninfected (A),uninfected treated with lovastatin(B),PbA-infected (C), andPbA-infected treated withlovastatin (D).

Vascular congestion and edema(*) were observed in PbA-

infected mice, but were not seenin controls or treated animals.


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IL-1, TNF- and IL-12 levels were elevated in brains ofmice showing CM.

These levels were reduced by lovastatin treatment (20mg/kg )

High levels of TNF- and MCP-1 (monocyte chemotacticprotein-1) were found in plasma which were reduced bytreatment with lovastatin.

Interestingly, RANTES (regulated and normal T cellexpressed and secreted) were not altered in infectedanimals nor were they affected in lovastatin treatment.


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CONCLUSION

Thus, lovastatin reduces the intracerebral and systemicinflammatory mediator responses in experimental CM.

Statins given as adjunct therapy to anti-plasmodial drugs,

it prevents cognitive impairment that follows cerebralmalaria.

Statins may be valuable pharmacological tool in treatingpatients with neuroinflammation associated with severe

systemic inflammatory syndromes.


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REFERENCES

Patricia A. Reis, Vanessa Estato, Tathiany I.da Silva, Joana C. D'Avila,Luciana D. Siqueira, Edson F. Assis, Patricia T. Bozza, Frenando A.Bozza, Eduardo V. Tibiricia, Guy A. Zimmerman, Hugo C. Castro-Faria-Neto(2012) Statins Decrease Neuroinflammation and Prevent CognitiveImpairment after Cerebral Malaria. PloS Pathogens.

Reis PA, Comim CM, hermaani F, Silva B, Barichello T, et.al. (2010)Cognitive dysfunction is sustained after rescued theraoy in experimentalcerebral malaria and is reduced by additive antioxidant therapy. PLoSPathogens.

Adela Nacer, Alexandru Movila, Kerstin Baer, Sebastian A. Mikolajczak,

Stefan H. I. Kappe, Ute Frevert mail (2012) Neuroimmunological BloodBrain Barrier Opening in Experimental Cerebral Malaria. PloSPathogens.

Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to thesite of inflammation: the leukocyte adhesion cascade updated. Nat RevImmunol 7

htt ://www.davidson.edu/academic/ s cholo /ramirezsite/neuroscience
http://www.davidson.edu/academic/psychology/ramirezsite/neuroscience/psy324/rebergner/what_is_cerebral_malaria.htmlhttp://www.davidson.edu/academic/psychology/ramirezsite/neuroscience/psy324/rebergner/what_is_cerebral_malaria.html


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Neurocognitive Protection by Statins in Cerebral Malaria