Proton magnetic resonance spectroscopy reveals neuroprotection by oral minocycline in a nonhuman primate model of accelerated NeuroAIDS.
BACKGROUND
Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury.


RESULTS
Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocycline-treated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals.


CONCLUSIONS
In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus.
Ratai
Eva-Maria
EM
AA Martinos Center for Biomedical Imaging and Neuroradiology Division, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. ratai@nmr.mgh.harvard.edu
Bombardier
Jeffrey P
JP
Joo
Chan-Gyu
CG
Annamalai
Lakshmanan
L
Burdo
Tricia H
TH
Campbell
Jennifer
J
Fell
Robert
R
Hakimelahi
Reza
R
He
Julian
J
Autissier
Patrick
P
Lentz
Margaret R
MR
Halpern
Elkan F
EF
Masliah
Eliezer
E
Williams
Kenneth C
KC
Westmoreland
Susan V
SV
González
R Gilberto
RG
D016263:AIDS-Associated Nephropathy / Q000150:complications / Q000517:prevention & control*; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008212:Lymphocyte Depletion; D008253:Macaca mulatta / Q000821:virology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017628:Microglia / Q000473:pathology / Q000821:virology; D008911:Minocycline / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011522:Protons; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D019562:Viral Load
D015415:Biomarkers; D004268:DNA-Binding Proteins; D018696:Neuroprotective Agents; D011522:Protons; D008911:Minocycline