Amphetamine and environmentally induced hyperthermia differentially alter the expression of genes regulating vascular tone and angiogenesis in the meninges and associated vasculature.
An amphetamine (AMPH) regimen that does not produce a prominent blood-brain barrier breakdown was shown to significantly alter the expression of genes regulating vascular tone, immune function, and angiogenesis in vasculature associated with arachnoid and pia membranes of the forebrain. Adult-male Sprague-Dawley rats were given either saline injections during environmentally-induced hyperthermia (EIH) or four doses of AMPH with 2 h between each dose (5, 7.5, 10, and 10 mg/kg d-AMPH, s.c.) that produced hyperthermia. Rats were sacrificed either 3 h or 1 day after dosing, and total RNA and protein was isolated from the meninges, arachnoid and pia membranes, and associated vasculature (MAV) that surround the forebrain. Vip, eNos, Drd1a, and Edn1 (genes regulating vascular tone) were increased by either EIH or AMPH to varying degrees in MAV, indicating that EIH and AMPH produce differential responses to enhance vasodilatation. AMPH, and EIH to a lesser extent, elicited a significant inflammatory response at 3 h as indicated by an increased MAV expression of cytokines Il1b, Il6, Ccl-2, Cxcl1, and Cxcl2. Also, genes related to heat shock/stress and disruption of vascular homeostasis such as Icam1 and Hsp72 were also observed. The increased expression of Ctgf and Timp1 and the decreased expression of Akt1, Anpep, and Mmp2 and Tek (genes involved in stimulating angiogenesis) from AMPH exposure suggest that angiogenesis was arrested or disrupted in MAV to a greater extent by AMPH compared to EIH. Alterations in vascular-related gene expression in the parietal cortex and striatum after AMPH were less in magnitude than in MAV, indicating less of a disruption of vascular homeostasis in these two regions. Changes in the levels of insulin-like growth factor binding proteins Igfbp1, 2, and 5 in MAV, compared to those in striatum and parietal cortex, imply an interaction between these regions to regulate the levels of insulin-like growth factor after AMPH damage. Thus, the vasculature and meninges surrounding the surface of the forebrain may be an important region in which AMPHs can disrupt vascular homeostasis.
Thomas
Monzy
M
US Food and Drug Administration, National Center for Toxicological Research, Division of Neurotoxicology, 3900 NCTR Road, Jefferson, Arkansas 72079, USA.
George
Nysia I
NI
Patterson
Tucker A
TA
Bowyer
John F
JF
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005334:Fever / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008578:Meninges; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism
C526316:CCN2 protein, rat; D000697:Central Nervous System Stimulants; D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D055513:Connective Tissue Growth Factor; D014660:Vasoactive Intestinal Peptide; D000661:Amphetamine