Neuropharmacology 40 (2001) 1019–1027 www.elsevier.com/locate/neuropharm Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator B. Legutko a, b,* , X. Li a , P. Skolnick 1,a a Eli Lilly and Co., Lilly Research Laboratories, Corporate Center, Indianapolis, IN 46285, USA b Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland Received 25 September 2000; received in revised form 2 January 2001; accepted 8 January 2001 Abstract The effects of a novel AMPA receptor potentiator (LY392098) on the expression of brain-derived neurotrophic factor (BDNF) were examined in primary neuron culture. The addition of either AMPA or LY392098 to cortical neurons elicited a time and concentration dependent increase in mRNA encoding BDNF. Moreover, co-addition of subeffective concentrations of AMPA (1 μM) and LY392098 (1 μM) resulted in dramatic increases in both BDNF mRNA (25-fold) and protein (7-fold) levels, whilst no changes in either NT-3 or NT-4 mRNA were detected. More modest (1.5–2.5-fold) elevations in BDNF mRNA and protein expression were also produced by combinations of AMPA and LY392098 in cerebellar granule cell neurons. In contrast, AMPA and LY392098, either alone or in combination, did not elevate BDNF mRNA levels in primary astroglial cultures. Maximum elevations in BDNF mRNA and protein were produced by 6–12 h of AMPA receptor activation 1–3 h of AMPA receptor activation were required to elevate BDNF mRNA levels. AMPA receptor-mediated increases in BDNF mRNA and protein were abolished by the AMPA antagonist, NBQX, but were unaffected by the NMDA antagonist, MK-801. In cortical neuron cultures, activation of both L-type Ca +2 channels and mitogen-activated protein (MAP) kinases contribute to AMPA receptor-mediated increases in BDNF mRNA. The ability of LY392098 to increase the expression of BDNF in primary neuron culture indicates this and related biarylpropylsulfonamides may be useful in the treatment of neuropsychiatric disorders.  2001 Elsevier Science Ltd. All rights reserved. Keywords: LY392098; BDNF; Primary neuron culture; AMPA receptors 1. Introduction Brain-derived neurotrophic factor (BDNF) is a mem- ber of the nerve growth factor (NGF) family of trophic factors (reviewed in Ebadi et al., 1997). While BDNF was first characterized as a survival and differentiation factor in primary neuron culture (reviewed in Hefti et al., 1989), this neurotrophin has now been demonstrated to produce a range of effects in the adult central nervous system. For example, BDNF promotes the survival and sprouting of serotonergic axons in rat brain following challenge with a selective serotonin neurotoxin * Corresponding author at Institute of Pharmacology, Polish Acad- emy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. Tel.: +48- 12-637-4022; fax: +48-12-637-4500. E-mail address: nflegutk@cyf-kr.edu.pl (B. Legutko). 1 Present address: DOV Pharmaceuticals, 433 Hackensack Avenue, Hackensack, NJ 07601, USA 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00006-5 (Mamounas et al., 1995) and markedly increases survival of dopaminergic neurons in substantia nigra following direct infusion of MPP + (Frim et al., 1994). Furthermore, BDNF administration has been reported to produce anal- gesia (Siuciak et al., 1994), elicit antidepressant-like effects in behavioral despair models (Siuciak et al., 1997), and reduce blood glucose in obese diabetic (db/db) mice (Ono et al., 1997). These findings indicate that strategies directed at elevating BDNF levels could be useful in the treatment of various pathological con- ditions. In principle, administration of recombinant BDNF is feasible (Ono et al., 1997; Siuciak et al., 1997), but enhancing the expression of this neurotrophic factor may be a more practical strategy for therapies directed at dis- orders of the central nervous system. While the regu- lation of BDNF expression is complex (Timmusk et al., 1993) and incompletely understood (Shieh et al., 1998; Tao et al., 1998), AMPA receptor activation has been