PPARγ activation prevents impairments in spatial memory and neurogenesis following transient illness

Abstract

The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused a 50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox-2 inhibition was ineffective while PPARγ activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS-produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory.

Desvenlafaxine May Accelerate Neuronal Maturation in the Dentate Gyri of Adult Male Rats

“…We have confirmed expected age- and inflammation-associated group differences in hippocampal neurogenesis in the adult rat and mouse using multiple injections of this 50 mg/kg BrdU dose [42], , which does not appear to induce cell death [5] or impact adult rodent health negatively [44].…”

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses

“…Of particular significance to the present discussion is the finding that acute LPS treatment diminished the number of new neurons generated (Ormerod et al, 2013), impaired the proliferation of hippocampal precursor cells (Fujioka and Akema, 2010), and transiently reduced BDNF and NGF levels in the cortex and hippocampus (Guan and Fang, 2006; Kranjac et al, 2012). Impairments of hippocampal neurogenesis induced by LPS were prevented by antidepressants (Peng et al, 2012) and, importantly, were completely blocked by the non-steroidal anti-inflammatory agent indomethacin, confirming the contribution of inflammatory processes to impairments of neurogenesis (Monje et al, 2003).…”

Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats

“…Indeed, lifelong or repeated pathogenic insults can dysregulate peripheral pro-inflammatory cytokine milieus (Banks et al, 2014; Batty et al, 2013; Cambier, 2005; Green et al, 2014; Krabbe et al, 2004; Lockhart et al, 2009; Rooney, 2014; Vasto et al, 2007; Wårdh and Wikström, 2014). Blood-borne and neural routes of communication between the peripheral and central nervous systems have been well-defined (Dinarello et al, 1988; Ericsson et al, 1994; Maier, 2003) and systemic immune challenge dramatically alters neural activity (Barrientos et al, 2015; Chapman et al, 2010; Maier and Watkins, 1998) and ablates the production of new highly excitable hippocampal granule neurons (Chen et al, 2011; Ekdahl et al, 2003; Ekdahl et al, 2009; Monje et al, 2002; Monje et al, 2003; Ormerod et al, 2013). Systemic inflammation can stimulate the de novo synthesis of brain parenchymal cytokines primarily by microglia (Layé et al, 1996; Nguyen et al, 1998; Van Dam et al, 1995) but also by other CNS cells (Liu et al, 2014; Vincent et al, 1998).…”

“…Chronic systemic inflammation and chronic neuroinflammation can compromise glia and synaptic mechanisms thought to underlie memory (Barrientos et al, 2015; Chapman et al, 2010; de Haas et al, 2007; de Rivero Vaccari et al, 2014; Foster, 1999; Godbout and Johnson, 2009; Hauss-Wegrzyniak et al, 2002) for review . Hippocampal neurogenesis has been linked to cognition, can decline with age and is ablated by neuroinflammation (Belarbi et al, 2012; Ekdahl et al, 2003; Kuhn et al, 1996; Monje et al, 2003; Monje et al, 2007; Ormerod et al, 2013; Speisman et al, 2013a; Valero et al, 2014). Finally chronic age-associated neuroinflammation may render microglia dystrophic and primed to respond to repeated insult leading to disrupted feedback that compromises their typically protective and regenerative effects on neurons (Barrientos et al, 2015; Chapman et al, 2010; Streit, 2006; Streit et al, 2008; Streit et al, 2004) and other CNS cell types (de Haas et al, 2007; de Rivero Vaccari et al, 2014; Mawhinney et al, 2011).…”