Treatment with dexamethasone and vitamin D₃ attenuates neuroinflammatory age‐related changes in rat hippocampus

Abstract

Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases

“…The microglial response in mice lacking PARP-1 expression or activity was blocked after Aβ 42 injection, compared to robust microglial activation in wild-type mice, thus confirming the protective role of PARP-1 genetic or pharmacological inhibition (Kauppinen et al, 2011). The age-related increase in cleavage of PARP-1 was all attenuated in hippocampal tissue prepared from Wistar rats that received dexamethasone and vitamin D 3 (Moore et al, 2007). These findings suggest that vitamin D down-regulates PARP-1 expression and thus may have a protective role in neurological disorders.…”

Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury‐induced cytokine response after excitotoxic damage

“…Age-related increases in hippocampal IL-1b levels have been extensively studied, and IL-1b overexpression has been correlated with increased signaling through the IL-1b receptor I (IL-1RI) and enhanced microglial activation (Griffin et al, 2006;Moore et al, 2007), with concomitant decreased values of the anti-inflammatory cytokine IL-4 and down-regulation of intracellular survival signals in neuronal cells Nolan et al, 2005). In agreement, increased hippocampal IL-1b in aging has been directly implicated in the decline of synaptic plasticity and impaired performance of cognitive tasks in aged rats because IL-1b inhibition induces an ameliora- tion and improved memory (Gemma et al, 2005;Maher et al, 2005).…”

How dependent is synaptic plasticity on microglial phenotype?

“…Interestingly, the deficit in LTP in aged animals is attenuated by CD200Fc (Cox et al, 2012), whereas both the agerelated and A-induced decrease in LTP is at least partially reversed by IL-4 (Lyons et al, 2007b;Nolan et al, 2005), which increases hippocampal expression of CD200 (Lyons et al, 2009b). The age-related deficit in LTP and accompanying increase in microglial activation, are also associated with decreased hippocampal expression of fractalkine (Lyons et al, 2009a) and IL-10 ( Moore et al, 2007). The relationship between neuroinflammation, particularly microglial activation, and impaired LTP, has been consolidated by the finding that strategies which attenuate microglial activation, including polyunsaturated fatty acids, statins or anti-inflammatory cytokines, also attenuate the loss of LTP (Adams et al, 1998); this is the case in a number of models in which LTP is decreased including in A-and LPStreated animals and in aged animals (Clarke et al, 2008;Clarke et al, 2007;Cowley et al, 2012;Kelly et al, 2001;Kelly et al, 2011;Nolan et al, 2005).…”

“…These interactions appear to function as 'off' signals as do secreted CD22 and fractalkine (Biber et al, 2007), neurotrophins and anti-inflammatory cytokines such as interleukin (IL)-10 and IL-4 (Biber et al, 2007;Lyons et al, 2007b). These factors attenuate changes induced in microglia by stimuli that include interferon- (IFN), LPS and Aβ (Clarke et al, 2008;Lyons et al, 2007b) and, interestingly, age-related decreases in expression of several of these 'off ' signals have been reported (Lyons et al, 2009a;Moore et al, 2007;Nolan et al, 2005). …”