SUMMARY The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage. Initiation of daily treatment with our recently reported lead agent, P7C3-S243, one day after blast-mediated TBI blocks axonal degeneration and preserves normal synaptic activity, learning and memory, and motor coordination in mice. We additionally report persistent neurologic deficits and acquisition of an anxiety-like phenotype in untreated animals eight months after blast exposure. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both, such as occurs in TBI.

Axonal degeneration is a prominent feature of many forms of neurodegeneration, and also an early event in blast-mediated traumatic brain injury (TBI), the signature injury of soldiers in Iraq and Afghanistan. It is not known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. The Wallerian degeneration slow strain (WldS) of mice is resistant to some forms of axonal degeneration because of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1). Here, we demonstrate that resistance of WldS mice to axonal degeneration after blast-mediated TBI is associated with preserved function in hippocampal-dependent spatial memory, cerebellar-dependent motor balance, and retinal and optic nerve–dependent visual function. Thus, early axonal degeneration is likely a critical driver of subsequent neurobehavioral complications of blast-mediated TBI. Future therapeutic strategies targeted specifically at mitigating axonal degeneration may provide a uniquely beneficial approach to treating patients suffering from the effects of blast-mediated TBI.

Abstract. The quantitative and qualitative changes of serum lipoproteins have been studied in twelve patients with untreated uncomplicated nephrotic syndrome. The lipoprotein disorders found in these patients were characterized by an elevation of VLDL (d < 1.006 g ml‐1), LDL (d 1.006–1.019 g ml‐1) and LDL2 (d 1.019–1.063 g ml‐1) and a diminution of HDL2 (d 1.063–1.125 g ml‐1). These changes were strictly correlated with the concentration of serum albumin and were more pronounced in the patients with serum albumin < 20 g l‐1. The study of the relationship among the concentrations of the various lipoprotein classes indicated that (i) the levels of VLDL and LDL1 were reciprocally related to that of the high density lipoproteins and (ii) the level of LDL2 rose with the moderately increased VLDL and LDL1 but at the high concentrations of VLDL and LDL1 observed in the severe nephrotic syndrome it did not show any further increase, suggesting a defect in the conversion of VLDL to LDL2. The nephrotic syndrome was associated with marked changes in the composition of all lipoprotein fractions which were found to contain more phospholipid but less protein than normal. Major changes in composition were observed in VLDL and LDL1 which were rich in esterified cholesterol and phopholipids and had an esterified cholesterol: triglyceride molar ratio (CE/TG) higher than the corresponding fractions of the control subjects. Furthermore, CE/TG ratio in these fractions increased as their serum concentration increased. These observations indicate that in severe, untreated uncomplicated nephrotic syndrome there is a progressive accumulation of d < 1.019 g ml‐1 lipoproteins rich in esterified cholesterol. Chemically these resemble VLDL and chylomicron remnants and are possibly related to some defect in the conversion of VLDL to LDL2.

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Primary cilia are microtubule-based organelles present on most cells that regulate many physiological processes, ranging from maintaining energy homeostasis to renal function. However, the role of these structures in the regulation of behavior remains unknown. To study the role of cilia in behavior, we employ mouse models of the human ciliopathy, Bardet-Biedl Syndrome (BBS). Here, we demonstrate that BBS mice have significant impairments in context fear conditioning, a form of associative learning. Moreover, we show that postnatal deletion of BBS gene function, as well as congenital deletion, specifically in the forebrain, impairs context fear conditioning. Analyses indicated that these behavioral impairments are not the result of impaired hippocampal long-term potentiation. However, our results indicate that these behavioral impairments are the result of impaired hippocampal neurogenesis. Two-week treatment with lithium chloride partially restores the proliferation of hippocampal neurons which leads to a rescue of context fear conditioning. Overall, our results identify a novel role of cilia genes in hippocampal neurogenesis and long-term context fear conditioning.