title: Mildronate enhances learning/memory and changes hippocampal protein expression in trained rats.
abstract: Previously we demonstrated that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a representative of the aza-butyrobetaine class of compounds, protects mitochondrial metabolism under conditions such as ischemia. Mildronate also acted as a neuroprotective agent in an azidothymidine-induced mouse model of neurotoxicity, as well as in a rat model of Parkinson's disease. These observations suggest that mildronate may stimulate processes involved in cell survival and change expression of proteins involved in neurogenic processes. The present study investigated the influence of mildronate on learning and memory in the passive avoidance response (PAR) test and the active conditioned avoidance response (CAR) test in rats. The CAR test employed also bromodeoxyuridine (BrdU)-treated animals. Hippocampal cell BrdU incorporation was then immunohistochemically assessed in BrdU-treated, CAR-trained rats to identify proliferating cells. In addition, the expression of hippocampal proteins which could serve as memory enhancement biomarkers was evaluated and compared to non-trained animals' data. These biomarkers included glutamic acid decarboxylase 65/67 (GAD65/67), acetylcholine esterase (AChE), growth-associated protein-43 (GAP-43) and the transcription factor c-jun/activator protein-1 (AP-1). The results showed that mildronate enhanced learning/memory formation that coincided with the proliferation of neural progenitor cells, changing/regulating of the expression of biomarker proteins which are involved in the activation of glutamatergic and cholinergic pathways, transcription factors and adhesion molecule. The data from our study suggest that mildronate may be useful as a possible cognitive enhancer for the treatment of patients with neurodegenerative diseases with dementia.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Latvia; 1A Sarlotes St., Riga, LV-1001, Latvia. vijaklus@latnet.lv
authors.forename: Vija
authors.initials: V
authors.lastname: Klusa
authors.forename: Ruta
authors.initials: R
authors.lastname: Muceniece
authors.forename: Sergejs
authors.initials: S
authors.lastname: Isajevs
authors.forename: Darja
authors.initials: D
authors.lastname: Isajeva
authors.forename: Ulrika
authors.initials: U
authors.lastname: Beitnere
authors.forename: Ilona
authors.initials: I
authors.lastname: Mandrika
authors.forename: Jolanta
authors.initials: J
authors.lastname: Pupure
authors.forename: Juris
authors.initials: J
authors.lastname: Rumaks
authors.forename: Baiba
authors.initials: B
authors.lastname: Jansone
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008763:Methylhydrazines / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008763:Methylhydrazines; D009419:Nerve Tissue Proteins; C050147:3-(2,2,2-trimethylhydrazine)propionate; D000110:Acetylcholinesterase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D001973:Bromodeoxyuridine