Peroxisome proliferator-activated receptors (PPAR) are a group of ligand-activated transcription factors belonging to the nuclear receptor superfamily that is expressed ubiquitously throughout the human body. By forming a heterodimer coactivator complex with the retinoid X receptor (RXR), activated PPARs bind to DNA sequences, known as peroxisome proliferator response elements, in target promoter genes to regulate the transactivation of mitochondrial and peroxisome genes involved in multiple protein networks that regulate cellular metabolism and energy homeostasis ^[1][2][3][4][1,2,3,4]. In the absence of activating ligands, PPAR–RXR heterodimers are associated with a co-repressor complex that results in the repressed expression of key metabolic genes ^[4][5][4,5]. Three isoforms of PPAR have been identified: PPARα, PPAR β/δ, and PPARγ. All three isoforms play important roles in energy metabolism and storage, but they have different expression patterns and specific functions which have only a limited overlap. PPARα is highly expressed in metabolically active tissues, particularly in the liver, where it plays a major role in fatty acid (FA) metabolism to actively lower lipid levels ^[5][6][5,6]. PPARα also plays a role in ketogenesis by reducing plasma triglyceride levels and increasing high-density lipoprotein levels [4]. PPAR β/δ has a role in FA oxidation in skeletal and cardiac muscle and also helps to regulate blood glucose and cholesterol levels [6]. PPARγ is highly expressed in both white and brown adipose tissue, where it plays a key role in adipogenesis and is a potent modulator of whole-body lipid metabolism and insulin sensitivity [7]; it is also expressed in the skeletal muscle, liver, heart, and intestine [8], and in brain cells such as neurons and glia [9]. The actions of PPARγ include crosstalk with several other important pathways involved in regulating systemic energy homeostasis. For example, PPARγ and the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) play a key role in the co-regulation of mitochondrial oxidative metabolism induction [4].

All three PPAR isoforms are also expressed in the brain, where as well as regulating the expression of target genes implicated in glucose, lipid, and energy metabolism, they also promote axonal growth, oligodendrocyte formation and differentiation, and neuronal differentiation ^[10][11][10,11]. Among the three isoforms, PPARγ is the key neuronal isoform in the CNS. It plays a major role in neuroprotection by preventing neuroinflammation, regulates energy homeostasis, and regulates genes involved in FA metabolism including genes for acetyl-CoA carboxylase, FA synthase, and carnitine palmitoyltransferase 1 [12]. Illustrating its role in regulating metabolism, the overexpression of PPARγ in the rodent brain has been shown to increase food intake and abdominal fat ^[12][13][12,13].

Under physiological conditions, immunohistochemical studies in rodents and humans have demonstrated the expression of PPARγ in both neurons and glial cells in a number of important brain regions including the prefrontal cortex, basal ganglia, thalamus, and hippocampus ^[14][15][14,15]. Colocalization studies using immunofluorescence have demonstrated that in mice, PPARγ expression is higher in neurons than in astrocytes or microglia across most brain regions; PPARγ colocalization with astrocytes varied between 3.4% in the prefrontal cortex and 26.7% in the nucleus accumbens, and colocalization was consistently low with microglia across the brain regions [15]. Similar results were seen in the human brain with PPARγ showing colocalization with both neurons and astrocytes but not microglia [15]. Interestingly, when a lipopolysaccharide (LPS) was administered to induce a strong neuroimmune response in mice, PPARγ expression was observed in microglia, suggesting that expression may be regulated by the microglial functional state and increased in activated microglial cells [15]. Further evidence to support a role for PPARγ in activated microglia was demonstrated by Song and colleagues who showed that adiponectin regulates the function and polarization of microglia through PPARγ signaling by inducing a switch to the neuroprotective M2 phenotype in response to amyloid β toxicity [16]. These data point towards a potentially important role for PPARγ in mediating anti-inflammatory and neuroprotective effects in the brain ^[17][18][19][17,18,19].

Inflammation is characterized by the activation of macrophages and monocytes at sites of cellular or tissue damage and the subsequent release of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL-6), and IL-1β, which in turn leads to the stimulation of cyclooxygenase 2 and the production of prostaglandins via the breakdown of arachidonic acid [20]. Indeed, studies have provided evidence that the ligand-mediated activation of PPARγ is associated with a reduction in the accumulation of macrophages and the expression of inflammatory markers in vascular tissue in a mouse model of atherosclerosis [2]. Recently, it has been recognized that PPARγ is a key mediator of the immune response via its ability to inhibit the expression of proinflammatory cytokines, chemokines, and adhesion molecules in peripheral immune cells and resident cells [21], as well as its ability to direct the differentiation of immune cells towards anti-inflammatory phenotypes ^[5][22][5,22].

Neuroinflammation is a protective mechanism that activates pathways necessary to promote the removal of toxic agents released following cellular injury, helping to promote tissue repair and the removal of cellular debris. However, sustained inflammatory responses in the brain are damaging and can inhibit recovery from injury and promote cellular death. Persistent and abnormal neuroinflammatory responses can be triggered by both endogenous and environmental factors. In ischemic stroke, traumatic brain injury, and spinal cord injury, the activation of PPARγ attenuates inflammation by inhibiting the expression of proinflammatory mediators in microglia and macrophages [1]. Following a controlled cortical impact traumatic brain injury in mice, the PPARγ agonist pioglitazone was able to inhibit inflammatory marker genes including TNF-α, inducible nitric oxide synthase (iNOS), IL-1β, and IL-6 and reduce histological damage and inflammation in a dose-dependent manner (reviewed in [17]). Another PPARγ agonist, rosiglitazone, failed to reproduce these effects [23]. In a separate study by Niino and colleagues, the PPARγ agonist troglitazone attenuated the inflammation and clinical symptoms of experimental autoimmune encephalomyelitis (EAE) induced by the administration of myelin oligodendrocyte glycoprotein peptide 35–55 in mice via a postulated reduction in the expression of proinflammatory cytokine genes [24]. In addition, PPARγ is involved in the long-term promotion of cellular and tissue repair and the rescue of brain cells following injury including ischemic stroke, hemorrhagic stroke, traumatic brain injury, and spinal cord injury [1]. Consequently, PPARγ is viewed as an interesting target for therapeutic intervention in patients with brain injuries and neurodegenerative diseases.

Chronic inflammatory damage to the lipid-rich, insulating myelin sheath surrounding axons impairs nerve conduction ^[25][26][25,26]. Demyelination—the pathological process of myelin sheath loss from axons—can be caused by direct injury to the oligodendrocytes [27] that produce the myelin and provide trophic and metabolic support to axons. The oligodendrocyte injury may be amplified by the inflammatory responses to CNS tissue damage, accelerating disease progression.

Therefore, therapeutic strategies that target oligodendrocytes or enhance the proliferation of oligodendrocyte progenitor cells (OPCs) to promote remyelination, and thereby restore signal conduction [28] and functional deficits [29], are attractive in neuroinflammatory and neurodegenerative diseases [30]. PPARγ agonists may protect OPCs by preserving their integrity and by enabling their differentiation into mature myelin-forming cells. Thus, PPARγ agonists have the potential to promote recovery from demyelination through direct effects on oligodendrocytes ^{[20][21][22][23][24][31]}[20,21,22,23,24,31]. The crucial role of the progression of neuroinflammation in CNS diseases is confirmed with hematopoietic stem cell transplantation (HSCT) procedures. HSCT can halt ongoing inflammatory processes by replacing hematopoietic-originated microglia with donor-derived myeloid precursors. Donor-derived myeloid cells can differentiate into microglia, mimicking their functions and counterbalancing the activated microglia, thereby decreasing neuroinflammation and increasing repair mechanisms such as remyelination [32]. HSCT has been efficacious in halting neuroinflammation in diseases including multiple sclerosis (MS), neuromyelitis optica spectrum disorder, myasthenia gravis, and cerebral adrenoleukodystrophy (cALD) [32].

Leriglitazone hydrochloride is a novel, neuroprotective, brain penetrant PPARγ full agonist consisting of the hydrochloride salt of the active metabolite M4 of pioglitazone. In contrast to pioglitazone and other Thiazolidinediones (TZDs), leriglitazone shows the ability to cross the blood–brain barrier (BBB) BBB to reach the CNS at effective and safe concentrations. So far, it is the first TZD compound that has been proven to reach the brain in a sufficient concentration to engage that target effectively. Leriglitazone has been validated in in vivo and in vitro preclinical models that cover most of the potential known effects of PPARγ receptor activation, with a particular focus on CNS indications. Recent studies using leriglitazone have also demonstrated a potential role for PPARγ in promoting axonal myelination, providing neuroprotection in both neurons and astrocytes, and preserving the integrity of the BBB.

A phase 2 trial of leriglitazone in men and women with Friedreich’s ataxia (FRDA) (FRAMES; NCT 03917225) ^[33] [33] and a phase 2/3 trial of leriglitazone in men with AMN (ADVANCE; NCT03231878) have recently been completed [34]. A phase 2/3 open-label clinical study (NEXUS) in pediatric patients with early-stage cerebral ALD (cALD) (EUDRACT number 2019-000654-59) is currently in progress in Europe.

PPARγ agonists act simultaneously on several cellular metabolism and repair processes in the CNS that become dysfunctional because of cellular damage caused by neuroinflammatory and neurodegenerative diseases.