Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a chronic and recurrent condition marked by inflammation in the digestive tract [1]. Inflammatory bowel disease is generally associated with significant physical and psychological burdens [2]. A remarkable percentage of IBD patients might suffer from comorbid psychological conditions, such as depression and anxiety [3]. The prevalence rate of depression in individuals with IBD has been estimated to be twice that of the general population [4]. Several common molecular and cellular pathways including immuno-inflammatory pathways, oxidative stress, autoimmune responses, activation of the kynurenine pathway (KP) in tryptophan metabolism, and disturbance of the microbiome-gut-brain axis have been detected in the pathophysiology of IBD and depression, suggesting a bi-directional relationship between the brain and the gut [3], [5], [6].

The autoimmune nature of IBD indicates that inflammation and its related pathways play a crucial role in the development of this disease [7]. In IBD patients, immunological responses provoke the activation of nuclear factor kappa-B (NF-κB), resulting in the up-regulation of pro-inflammatory cytokines which include interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) [8], [9]. Moreover, the inflammatory responses in IBD disrupt the normal function of the gut barrier and destroy tight junction proteins, including zonula occludens (ZO-1) and claudin, consequently causing a rise in intestinal permeability [10], [11]. As a result, inflammatory cytokines leak from the inflamed intestine into the systemic circulation, cross the blood–brain barrier (BBB) and cause neuroinflammation [12]. Furthermore, the damaged tight junctions allow other inflammatory mediators, such as lipopolysaccharide (LPS), to enter the bloodstream and exacerbate systemic inflammation and subsequent neuroinflammation. The exposure of brain neurons to LPS could be associated with neuroinflammation and neurodegeneration [13].

The kynurenine pathway, the most dominant pathway in tryptophan metabolism, plays a principal role in both IBD and associated depression [14]. Indoleamine 2,3-dioxygenase (IDO) plays a fundamental role in KP by converting tryptophan to kynurenine. It has been reported that the up-regulation of inflammatory markers which includes IFN-γ, TNF-α, IL-6, and IL-1β or peripheral inflammatory mediators, such as LPS, can induce the activity of IDO [14], [15]. Kynurenic acid (KYNA) and quinolinic acid (QUIN) are known as two major downstream metabolites of kynurenine in KP [16]. Earlier investigations demonstrate that there is a direct relationship between the level of KP metabolites and the severity of intestinal inflammation in IBD patients [17], [18]. In addition, it has been noted that IDO dysfunction is associated with depressive-like behaviors in both humans and animals [19].

According to previous studies, QUIN has been found to trigger oxidative stress and cell death by stimulating the generation of free radicals [20]. It has been observed that the level of this metabolite increases in depression [21]. Nevertheless, KYNA is an NMDA receptor antagonist and shows antioxidant and neuroprotective effects [22]. In this regard, stabilizing the KYNA/QUIN ratio has been suggested as a neuroprotective factor that has an inverse relationship with depressive-like behaviors [23]. The neurotoxic effects of pro-inflammatory cytokines, imbalance between KP metabolite production in the hippocampus, and impairment of the BBB function can lead to disturbances in the neurogenesis and normal homeostasis of the hippocampal neurons, which can be associated with behavioral changes [24], [25]. Therefore, it seems that inflammation-induced depression could be one of the potential mechanisms for the co-occurrence of depression with IBD [26].

Aripiprazole (ARP), as an atypical antipsychotic, was approved for treating schizophrenia. In addition, it was observed to be effective in manic and bipolar disorders [27]. Aripiprazole reveals antipsychotic activity by modulating dopamine receptor type 2 (D2R). Numerous studies have emphasized the differential effects of ARP on dopaminergic signaling and multiple receptors and signaling pathways [28]. Many other neurotransmitter systems, such as adrenergic pathways, histaminergic pathways, and serotonergic receptors (5-HTR), are affected by ARP [29], [30]. According to previous clinical studies, ARP can be used in major depressive disorder, depression episodes in bipolar disorder, treatment-resistant depression, and probably anxiety disorders [31] by affecting serotonin-1A (5-HT1A), 5-HT2, D2, and D3 receptors [32].

Behind the regulating effects of ARP on the neural transmission system and subsequent antipsychotic and anti-depressant actions, it shows various direct and indirect anti-inflammatory properties in experimental studies [33], [34], [35]. Several studies have demonstrated that the ameliorative effects of ARP in the animal models of spinal cord injury, stress-induced depression, cerebral ischemia, and renal ischemia are due to its anti-inflammatory effects [26], [35], [36]. It has been demonstrated that the primary mechanism by which ARP reduces inflammation is through suppressing the production of cytokines, such as IL-1β and TNF-α, and inhibiting microglia and astrocyte activation [37], [38], [39]. Likewise, ARP was shown to induce protective effects on vincristine-induced neuropathy through the inhibition of NF-κB activity [40]. The emphasis on the anti-inflammatory properties of ARP has made it a potential option for repositioning in inflammatory disorders, such as IBD [41]. The hippocampus regions are the most important parts of the brain in depressive disorders. Its central roles in depressive-like behaviors were previously confirmed.

In this regard, many researchers have examined the hippocampus functions and structure for evaluating different types of depression-like behaviors in experimental studies [42], [43]. Investigating the hippocampus in the context of IBD-associated depressive-like behaviors provides valuable insights into the underlying mechanisms of ARP on mood disturbances in IBD-induced depression.

Despite ample evidence supporting the anti-inflammatory effects of ARP, its potential protective and anti-inflammatory effects on IBD have not been explored to date. Our study aimed to investigate the novel role of ARP on the NF-κB/kynurenine pathway in the context of IBD using a TNBS-induced colitis animal model. Moreover, we uniquely proposed to explore the interaction between the KP and pro-inflammatory cytokines in IBD-associated depression. Accordingly, we focused on evaluating the protective effects of ARP against TNBS-induced colitis and depressive-like behaviors, as the first study to address this gap.