This restriction protects neural tissues from toxins and pathogens. Tight junctions exist between the endothelial cells of the BBB, which restrict para-cellular movement and diffusion of solutes in the blood. Blood-brain barrier (BBB) dysfunction leads to dysregulation of ions, altered homeostasis signaling, and introduction of molecules and toxins into the CNS, leading to homeostatic imbalances and neurodegeneration. In addition, altered levels of cytokines induced by lipopolysaccharides (LPS) and free radicals, such as TNF-α and IFN-γ, are involved in the induction of oxidative stress and are also associated with the pathophysiology of NDs. Several types of ND, such as AD, PD, and ALS share similar pathological, genetic, and molecular mechanisms of disease manifestation. The cerebral spinal fluid and plasma levels of tryptophan are both depleted in ALS patients. ALS is a multifactorial ND characterized by the depletion of neuronal function in the spinal cord and brain. KPM levels are dysregulated in neurodegenerative diseases (ND), including amyotrophic lateral sclerosis (ALS). KP metabolites (KPM) are used as diagnostic markers for the progression, severity, and prognosis of diseases of the nervous system. Therefore, balanced production of kynurenic and quinolinic acids is important for the prevention of neurodegenerative and psychiatric disorders. However, another byproduct of this pathway is kynurenic acid, an NMDA antagonist, which helps prevent neuronal damage. KP byproduct such as quinolinic acid (an agonist of the N-methyl- d-aspartate (NMDA) receptor) cause neuronal dysfunction an elevated level of quinolinic acid is indicative of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, autoimmune disease, psychiatric disease, epilepsy, and other infectious diseases. Inflammatory cytokines, specifically interferon-γ (IFN-γ), and others, such as tumor necrosis factor-alpha (TNF-α), and free radicals also alter IDO levels. An increase in IDO activity alters serotonin production, leading to the production of kynurenine and neuroactive catabolites, which are either neuroprotective or neurotoxic. The kynurenine pathway (KP) converts tryptophan to kynurenine with the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), which are involved in the development and prevention of inflammation in the brain. Serotonin is a neurotransmitter involved in sensory and motor functions and the regulation of emotions. Tryptophan, an essential amino acid for protein biosynthesis, is converted into bioactive metabolites such as serotonin, melatonin, and kynurenine to regulate several physiological processes. The tryptophan transport system may provide a therapeutic target for treating or preventing neurodegenerative diseases. However, treatment with neuroprotective drugs ameliorated tryptophan uptake by NSC-34 cell lines after inflammatory cytokines pretreatment. In addition, tryptophan uptake was increased by TR-BBB cell lines but decreased by NSC-34 cell lines after pro-inflammatory cytokine pre-treatment. Gene knockdown of LAT1 ( l-type amino acid transporter 1) and CAT1 (cationic amino acid transporter 1) demonstrated that LAT1 is primarily involved in the transport of l-tryptophan in both TR-BBB and NSC-34 cell lines. Additionally, l-tryptophan uptake was time- and concentration-dependent in both NSC-34 wild type (WT) and mutant type (MT) cell lines, with a lower transporter affinity and higher capacity in MT than in WT cell lines. Gabapentin and baclofen exerted a competitive inhibitory effect on l-tryptophan uptake. Transporter inhibitors and several neuroprotective drugs inhibited l-tryptophan uptake by TR-BBB cell lines. The uptake of l-tryptophan was stereospecific, and concentration- and sodium-dependent in TR-BBB cell lines. In this study, we investigated the transport mechanisms of tryptophan in brain capillary endothelial (TR-BBB) cell lines and motor neuron-like (NSC-34) cell lines. Tryptophan plays a key role in several neurological and psychiatric disorders.
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