title: Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats.
abstract: Mildronate (3-(2,2,2-trimethylhydrazinium) propionate) is an inhibitor of l-carnitine biosynthesis and an anti-ischemic drug. In the present study, we investigated the effects of mildronate in rats following focal cerebral ischemia. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90min, followed by the intraperitoneal administration of mildronate at doses of 100 and 200mg/kg 2h after reperfusion and then daily for an additional 14days. The beam-walking, rota-rod and cylinder tests were used to assess sensorimotor function, and vibrissae-evoked forelimb-placing and limb-placing tests examined responses to tactile and proprioceptive stimulation. Following behavioural testing, the infarct volume was measured. The cerebellar concentrations of l-carnitine, γ-butyrobetaine (GBB) and mildronate were also measured. The results showed that saline-treated MCAO rats had minor or no spontaneous recovery in sensorimotor and proprioceptive function up to 14days post-stroke. Treatment with mildronate at a dose of 200mg/kg was found to accelerate recovery of motor and proprioceptive deficits in limb-placing, cylinder and beam-walking tests. Analysis of rat cerebellar tissue extracts revealed that l-carnitine and GBB concentrations changed with mildronate treatment; the concentration of l-carnitine was significantly decreased by mildronate treatment, whereas the concentration of GBB was significantly increased. Cerebellar concentrations of mildronate also increased in a dose-dependent manner following systemic administration. Infarct size did not differ among the experimental groups on post-stroke day 14. The present study suggests that mildronate treatment improves the functional outcome in MCAO rats without influencing infarct size.
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia; University of Latvia, Riga, Latvia. svalbe@biomed.lu.lv
authors.forename: Baiba
authors.initials: B
authors.lastname: Svalbe
authors.forename: Liga
authors.initials: L
authors.lastname: Zvejniece
authors.forename: Edijs
authors.initials: E
authors.lastname: Vavers
authors.forename: Osvalds
authors.initials: O
authors.lastname: Pugovics
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002331:Carnitine / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005121:Extremities / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008763:Methylhydrazines / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D045442:Rotarod Performance Test; D053719:Tandem Mass Spectrometry / Q000379:methods; D014738:Vibrissae / Q000294:innervation
chemical_list: D000276:Adjuvants, Immunologic; D008763:Methylhydrazines; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002331:Carnitine