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<p>Hyperammonemia (HA) is a metabolic disorder characterized by elevated ammonia levels in the blood. Ammonia produced from the metabolism of amino acids is mainly detoxified in the liver through the urea cycle. However, defects in this cycle result in the buildup of ammonia in the blood, which is highly neurotoxic and disrupts multiple signaling pathways in the brain, including nitric oxide (NO). NO is produced from the enzyme nitric oxide synthase (NOS), which exists in three different isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). NO is an important signaling molecule that plays a crucial role in various physiological functions, like neurotransmission, synaptic plasticity, learning and memory, regulation of cerebral blood flow, and immune responses. The role of NO in HA pathophysiology remains debated, with evidence supporting both neurotoxic and neuroprotective effects. The present review explains the relationship between HA and different NOS isoforms in the discrete brain regions, highlighting their effects on NO production in both acute and chronic HA conditions. HA impairs the glutamate-NO-cGMP pathway through multiple mechanisms, including tonic NMDAR activation, CaMKII-mediated modulation of nNOS, neurosteroids, and neurotransmitter imbalances. Moreover, alterations in arginine transport via the y⁺LAT2 transporter, and elevated levels of methylarginine derivatives, such as asymmetric dimethylarginine, contribute to reduced NOS activity, leading to reduced NO production, increased oxidative stress, and an increased inflammatory response in HA. Understanding these multiple mechanisms underlying NOS modulation may provide new therapeutic strategies to improve neurological impairments associated with HA. </p>

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Nitric Oxide Synthase Dysregulation in Hyperammonemia: Opportunities and Challenges Toward Therapeutic Targeting to Combat Neurological Complications

  • 期刊论文

  • 发表日期：

    2026年2月28日

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  • Poonam Dhiman,
  • Rajneesh Kumar,
  • Damanpreet Singh

摘要

Hyperammonemia (HA) is a metabolic disorder characterized by elevated ammonia levels in the blood. Ammonia produced from the metabolism of amino acids is mainly detoxified in the liver through the urea cycle. However, defects in this cycle result in the buildup of ammonia in the blood, which is highly neurotoxic and disrupts multiple signaling pathways in the brain, including nitric oxide (NO). NO is produced from the enzyme nitric oxide synthase (NOS), which exists in three different isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). NO is an important signaling molecule that plays a crucial role in various physiological functions, like neurotransmission, synaptic plasticity, learning and memory, regulation of cerebral blood flow, and immune responses. The role of NO in HA pathophysiology remains debated, with evidence supporting both neurotoxic and neuroprotective effects. The present review explains the relationship between HA and different NOS isoforms in the discrete brain regions, highlighting their effects on NO production in both acute and chronic HA conditions. HA impairs the glutamate-NO-cGMP pathway through multiple mechanisms, including tonic NMDAR activation, CaMKII-mediated modulation of nNOS, neurosteroids, and neurotransmitter imbalances. Moreover, alterations in arginine transport via the y⁺LAT2 transporter, and elevated levels of methylarginine derivatives, such as asymmetric dimethylarginine, contribute to reduced NOS activity, leading to reduced NO production, increased oxidative stress, and an increased inflammatory response in HA. Understanding these multiple mechanisms underlying NOS modulation may provide new therapeutic strategies to improve neurological impairments associated with HA.