Michael K. Racke

Paul D. Drew

PPARs in Neuroinflammation

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPAR<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M1" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
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</svg>, <svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg>, and <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M3" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,10.7375)">
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				<tspan style="font-size: 12.50px; " x="0" y="0">𝛿</tspan>
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		</g>
	</g>
</svg> isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer&#x27;s disease, Parkinson&#x27;s disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-<svg style="vertical-align:-0.0pt;width:9.4125004px;" id="M4" height="7.0124998" version="1.1" viewBox="0 0 9.4125004 7.0124998" width="9.4125004"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.0125)">
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				<tspan style="font-size: 12.50px; " x="0" y="0">𝜅</tspan>
			</text>

		</g>
	</g>
</svg>B and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.

John J. Bright

Saravanan Kanakasabai

Wanida Chearwae

Sharmistha Chakraborty

PPAR Regulation of Inflammatory Signaling in CNS Diseases

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M1" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
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			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

		</g>
	</g>
</svg> regulation of the immune response. We describe how PPAR-<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M2" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
		<g transform="translate(72,-66.26)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

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</svg> regulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M3" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,7.175)">
		<g transform="translate(72,-66.26)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛼</tspan>
			</text>

		</g>
	</g>
</svg> agonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis.

Yuhong Yang

Anne R. Gocke

Amy Lovett-Racke

PPAR Alpha Regulation of the Immune Response and Autoimmune Encephalomyelitis

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer&#x27;s, and Parkinson&#x27;s disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer&#x27;s disease (AD) is triggered by the neurodegeneration and the deposition of the <svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M1" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,13.425)">
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			<text transform="matrix(1,0,0,-1,-71.95,63.6)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛽</tspan>
			</text>

		</g>
	</g>
</svg>-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer&#x27;s disease, while they also directly activate PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
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			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

		</g>
	</g>
</svg>. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
		<g transform="translate(72,-64.05)">
			<text transform="matrix(1,0,0,-1,-71.95,66.44)">
				<tspan style="font-size: 12.50px; " x="0" y="0">𝛾</tspan>
			</text>

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	</g>
</svg>. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPAR<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
	<g transform="matrix(1.25,0,0,-1.25,0,9.9375)">
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</svg> receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.

Markus P. Kummer

Michael T. Heneka

PPARs in Alzheimer&#39;s Disease

Accumulation of amyloid-<svg     style="vertical-align:-3.56265pt;width:10px;" id="M4" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> peptide (A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M5" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>) appears to contribute to the pathogenesis of Alzheimer&#x27;s disease (AD). Therapeutic hope for the prevention or removal of 
A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M6" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>  deposits has been placed in strategies involving immunization against the A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M7" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> peptide.  Initial A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M8" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg> immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M9" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>. Specifically, <svg     style="vertical-align:-0.20473pt;width:39.6875px;" id="M10" height="14.375" version="1.1" viewBox="0 0 39.6875 14.375" width="39.6875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M11" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg> immunization in the treatment of AD.  Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, A<svg     style="vertical-align:-4.0404pt;width:32px;" id="M12" height="17.262501" version="1.1" viewBox="0 0 32 17.262501" width="32"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

			<g transform="matrix(.012,-0,0,-.012,9.938,17.2)"><use xlink:href="#x31"/></g>

			<g transform="matrix(.012,-0,0,-.012,15.65,17.2)"><path id="x2D" d="M300 253l-14 -55h-229l14 55h229z" /></g>

			<g transform="matrix(.012,-0,0,-.012,19.887,17.2)"><use xlink:href="#x34"/></g><g transform="matrix(.012,-0,0,-.012,25.599,17.2)"><use xlink:href="#x32"/></g>

		
	
</svg> synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M13" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g>

		
	
</svg> agonist 15-deoxy-<svg     style="vertical-align:-0.0pt;width:37.200001px;" id="M14" height="15.8375" version="1.1" viewBox="0 0 37.200001 15.8375" width="37.200001"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,15.775)"><path id="x394" d="M600 0h-557v24l268 633l28 8l261 -641v-24zM497 50l-194 489l-196 -489h390z" /></g>

			<g transform="matrix(.012,-0,0,-.012,10.963,7.613)"><use xlink:href="#x31"/></g><g transform="matrix(.012,-0,0,-.012,16.674,7.613)"><use xlink:href="#x32"/></g><g transform="matrix(.012,-0,0,-.012,22.385,7.613)"><use xlink:href="#x2C"/></g><g transform="matrix(.012,-0,0,-.012,25.098,7.613)"><use xlink:href="#x31"/></g><g transform="matrix(.012,-0,0,-.012,30.81,7.613)"><use xlink:href="#x34"/></g>

		
	
</svg>-<svg     style="vertical-align:-3.27605pt;width:33.775002px;" id="M15" height="15.5125" version="1.1" viewBox="0 0 33.775002 15.5125" width="33.775002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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			<g transform="matrix(.012,-0,0,-.012,27.375,15.45)"><use xlink:href="#x32"/></g>

		
	
</svg> (15d-<svg     style="vertical-align:-3.27605pt;width:33.775002px;" id="M16" height="15.5125" version="1.1" viewBox="0 0 33.775002 15.5125" width="33.775002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.363)"><use xlink:href="#x50"/></g><g transform="matrix(.017,-0,0,-.017,9.633,11.363)"><use xlink:href="#x47"/></g><g transform="matrix(.017,-0,0,-.017,21.787,11.363)"><use xlink:href="#x4A"/></g>

			<g transform="matrix(.012,-0,0,-.012,27.375,15.45)"><use xlink:href="#x32"/></g>

		
	
</svg>) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-<svg     style="vertical-align:-3.27605pt;width:33.775002px;" id="M17" height="15.5125" version="1.1" viewBox="0 0 33.775002 15.5125" width="33.775002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.363)"><use xlink:href="#x50"/></g><g transform="matrix(.017,-0,0,-.017,9.633,11.363)"><use xlink:href="#x47"/></g><g transform="matrix(.017,-0,0,-.017,21.787,11.363)"><use xlink:href="#x4A"/></g>

			<g transform="matrix(.012,-0,0,-.012,27.375,15.45)"><use xlink:href="#x32"/></g>

		
	
</svg> suppressed the A<svg     style="vertical-align:-3.56265pt;width:10px;" id="M18" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M19" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> agonists may be effective in modulating the development of AD.

Jihong Xu

Steven W. Barger

The PPAR-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> Agonist 15-Deoxy-<svg style="vertical-align:-0.0pt" height="15.8375" version="1.1" viewBox="0 0 38.049999 15.8375" width="38.049999" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,15.775)"><path id="x1D6AB" d="M340 690l316 -690h-640l296 690h28zM111 120h320l-165 359z"/></g><g transform="matrix(.012,-0,0,-.012,11.813,7.613)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z"/></g><g transform="matrix(.012,-0,0,-.012,17.524,7.613)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z"/></g><g transform="matrix(.012,-0,0,-.012,23.238,7.613)"><path id="x2C" d="M95 130q31 0 61 -30t30 -78q0 -53 -38 -87.5t-93 -51.5l-11 29q77 31 77 85q0 26 -17.5 43t-44.5 24q-4 0 -8.5 6.5t-4.5 17.5q0 18 15 30t34 12z"/></g><g transform="matrix(.012,-0,0,-.012,25.95,7.613)"><use xlink:href="#x31"/></g><g transform="matrix(.012,-0,0,-.012,31.661,7.613)"><path id="x34" d="M456 178h-96v-72q0 -51 12.5 -62.5t72.5 -16.5v-27h-256v27q65 5 78 17t13 62v72h-260v28q182 271 300 426h40v-407h96v-47zM280 225v295h-2q-107 -148 -196 -295h198z"/></g></svg>-Prostaglandin <svg style="vertical-align:-3.27605pt" height="15.25" version="1.1" viewBox="0 0 12.05 15.25" width="12.05" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x4A" d="M303 650v-28q-58 -5 -71.5 -19.5t-13.5 -77.5v-373q0 -99 -18.5 -156.5t-67.5 -102.5q-49 -44 -93 -58l-12 29q78 38 96 130q10 60 10 191v340q0 63 -14 77.5t-75 19.5v28h259z"/></g><g transform="matrix(.012,-0,0,-.012,5.65,15.187)"><use xlink:href="#x32"/></g></svg> Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer&#x2019;s Disease

The role of peroxisome proliferator-activated receptors (PPARs) in altering lipid and glucose metabolism is well established. More recent studies indicate that PPARs also play critical roles in controlling immune responses. We and others have previously demonstrated that PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg> agonists modulate the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This review will discuss the cellular and molecular mechanisms by which these agonists are believed to modulate disease. The therapeutic potential of PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M3" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg> agonists in the treatment of multiple sclerosis will also be considered.

PPAR-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg>: Therapeutic Potential for Multiple Sclerosis

Microglia and astrocytes express numerous members of the Toll-like receptor (TLR) family that are pivotal for recognizing conserved microbial motifs expressed by a wide array of pathogens. Despite the critical role for TLRs in pathogen recognition, when dysregulated these pathways can also exacerbate CNS tissue destruction. Therefore, a critical balance must be achieved to elicit sufficient immunity to combat CNS infectious insults and down-regulate these responses to avoid pathological tissue damage. We performed a comprehensive survey on the efficacy of various PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M2" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> agonists to modulate proinflammatory mediator release from primary microglia and astrocytes in response to numerous TLR ligands relevant to CNS infectious diseases. The results demonstrated differential abilities of select PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> agonists to modulate glial activation. For example, 15d-PG<svg     style="vertical-align:-3.27605pt;width:12.05px;" id="M4" height="15.25" version="1.1" viewBox="0 0 12.05 15.25" width="12.05"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> and pioglitazone were both effective at reducing IL-12 p40 release by TLR ligand-activated glia, whereas CXCL2 expression was either augmented or inhibited by 15d-PG<svg     style="vertical-align:-3.27605pt;width:12.05px;" id="M5" height="15.25" version="1.1" viewBox="0 0 12.05 15.25" width="12.05"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>, effects that were dependent on the TLR ligand examined. Pioglitazone and troglitazone demonstrated opposing actions on microglial CCL2 production that were TLR ligand-dependent. Collectively, this information may be exploited to modulate the host immune response during CNS infections to maximize host immunity while minimizing inappropriate bystander tissue damage that is often characteristic of such diseases.

Catherine Gurley

Jessica Nichols

Shuliang Liu

Nirmal K. Phulwani

Nilufer Esen

Tammy Kielian

Microglia and Astrocyte Activation by Toll-Like Receptor Ligands: Modulation by PPAR-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> Agonists

Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100&#x2009;000 individuals.  It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M2" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g>

		
	
</svg> (PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M3" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington&#x27;s disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M4" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M5" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M6" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M7" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FE"/></g>

		
	
</svg> in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD.  PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M8" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> coactivator-1<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M9" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g>

		
	
</svg> (PGC-1<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M10" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M11" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> in the regulation of mitochondrial biogenesis. Therefore, PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M12" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1<svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M13" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>. In this review, the role of PPAR-<svg     style="vertical-align:-3.56265pt;width:8.6374998px;" id="M14" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> in ALS and HD is discussed based on the current literature and hypotheses.

Mahmoud Kiaei

Peroxisome Proliferator-Activated Receptor-<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> in Amyotrophic Lateral Sclerosis and Huntington&#x2019;s Disease

In the recent years, the peroxisome proliferator-activated receptor-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M2" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg>), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M4" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg> agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy <svg style="vertical-align:-0.0pt;width:36.650002px;" id="M5" height="13.95" version="1.1" viewBox="0 0 36.650002 13.95" width="36.650002"  xmlns="http://www.w3.org/2000/svg">
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</svg>), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer&#x27;s and  Parkinson&#x27;s diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M7" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg> agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-<svg style="vertical-align:-2.34499pt;width:8.0625px;" id="M8" height="9.9375" version="1.1" viewBox="0 0 8.0625 9.9375" width="8.0625"  xmlns="http://www.w3.org/2000/svg">
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</svg> agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

Antonietta Bernardo

Luisa Minghetti

Regulation of Glial Cell Functions by PPAR-<svg style="vertical-align:-2.7573pt" height="11.4125" version="1.1" viewBox="0 0 8.4499998 11.4125" width="8.4499998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.912)"><path id="x1D738" d="M377 450h126l-264 -401q0 -75 -21 -153q-12 -44 -36 -71t-56 -27q-27 0 -42 18.5t-15 42.5q0 34 30 89q9 16 32 50q21 31 29 46q13 91 13 208q0 45 -11 94q-11 47 -34 47q-38 0 -61 -81h-23q40 150 121 150q46 0 65 -34.5t19 -99.5q0 -54 -7 -125z" /></g></svg> Natural and Synthetic Agonists

Stroke (focal cerebral ischemia) is a leading cause of death and disability among adult population. Many pathological events including inflammation and oxidative stress during the acute period contributes to the secondary neuronal death leading the neurological dysfunction after stroke. Transcriptional regulation of genes that promote these pathophysiological mechanisms can be an effective strategy to minimize the poststroke neuronal death. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to be upstream to many inflammatory and antioxidant genes. The goal of this review is to discuss the therapeutic potential and putative mechanisms of neuroprotection following PPAR activation after stroke.

Raghu Vemuganti

Therapeutic Potential of PPAR<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z"/></g></svg> Activation in Stroke

About this journal

<p><em>PPAR Research</em> publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.</p>


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<p>Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.</p>


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PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

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PPAR Research | Hindawi

PPAR Research

<p>This Issue is now open for submissions.</p>
<p>Papers are published upon acceptance, regardless of the Special Issue publication date.</p>


PPAR Research

PPARs in Neuroinflammation

PPARs in Neuroinflammation

Articles