👤 Serena Ramji

Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Δex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Δex1-6) mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Δex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Δex1-6) mice. At a later stage of the disease, in 6-7-month-old Cln3(Δex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Δex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease. Show less

Liver X receptors (LXRs) are ligand-dependent transcription factors that are activated by metabolites of cholesterol, oxysterols, and a number of synthetic agonists. LXRs play potent anti-atherogenic roles in part by stimulating the efflux of cholesterol from macrophage foam cells. The LXR-induced expression of ATP-binding cassette transporter (ABC)-A1 and Apolipoprotein E (ApoE) in macrophages is essential for the stimulation of cholesterol efflux and the prevention of atherosclerotic development. Unfortunately, the signaling pathways underlying such regulation are poorly understood and were therefore investigated in human macrophages. The expression of ApoE and ABCA1 induced by synthetic or natural LXR ligands [TO901317, GW3965, and 22-(R)-hydroxycholesterol (22-(R)-HC), respectively] was attenuated by inhibitors of c-Jun N-terminal kinase (JNK) (curcumin and SP600125) and phosphoinositide 3-kinase (PI3K) (LY294002). Similar results were obtained with ABCG1 and LXR-α, two other LXR target genes. LXR agonists activated several components of the JNK pathway (SEK1, JNK and c-Jun) along with AKT, a downstream target for PI3K. In addition, dominant negative mutants of JNK and PI3K pathways inhibited the LXR-agonists-induced activity of the ABCA1 and LXR-α gene promoters in transfected cells. LXR agonists also induced the binding of activator protein-1 (AP-1), a key transcription factor family regulated by JNK, to recognition sequences present in the regulatory regions of the ApoE and ABCA1 genes. These studies reveal a novel role for JNK and PI3K/AKT signaling in the LXR-regulated expression in macrophages of several key genes implicated in atherosclerosis. Show less