Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy

Abstract As a cancer therapy, hypothermia has been used at sub-zero temperatures to cryosurgically ablate tumors. However, these temperatures can indiscriminately damage both tumorous and healthy cells. Additionally, strategies designed to kill tumor typically accelerate their evolution and recurrence can be inevitable in cancers such as glioblastoma (GBM). To bypass these limitations, here we studied the use of hypothermia as a cytostatic tool against cancer and deployed it against an aggressive rodent model of GBM. To identify the minimal dosage of ‘cytostatic hypothermia’, we cultured at least 4 GBM lines at 4 continuous or intermittent degrees of hypothermia and evaluated their growth rates through a custom imaging-based assay. This revealed cell-specific sensitivities to hypothermia. Subsequently, we examined the effects of cytostatic hypothermia on these cells by a cursory study of their cell-cycle, energy metabolism, and protein synthesis. Next, we investigated the use of cytostatic hypothermia as an adjuvant to chemotherapy and CAR T immunotherapy. Our studies demonstrated that cytostatic hypothermia did not interfere with Temozolomide in vitro and may have been synergistic against at least 1 GBM line. Interestingly, we also demonstrated that CAR T immunotherapy can function under cytostatic hypothermia. To assess the efficacy of hypothermia in vivo, we report the design of an implantable device to focally administer cytostatic hypothermia in an aggressive rodent model of F98 GBM. Cytostatic hypothermia significantly doubled the median survival of tumor-bearing rats with no obvious signs of distress. The absence of gross behavioral alterations is in concurrence with literature suggesting the brain is naturally resilient to focal hypothermia. Based on these findings, we anticipate that focally administered cytostatic hypothermia alone has the potential to delay tumor recurrence or increase progression-free survival in patients. Additionally, it could also provide more time to evaluate concomitant, curative cytotoxic treatments.

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A Comprehensive Review Evaluating the Impact of Protein Source (Vegetarian vs. Meat Based) in Hepatic Encephalopathy

Nutrients ◽

10.3390/nu13020370 ◽

2021 ◽

Vol 13 (2) ◽

pp. 370

Author(s):

Umair Iqbal ◽

Ravirajsinh N. Jadeja ◽

Harshit S. Khara ◽

Sandeep Khurana

Keyword(s):

Hepatic Encephalopathy ◽

Protein Intake ◽

Alternative Therapy ◽

Case Series ◽

Current Evidence ◽

Branch Chain Amino ◽

The Impact ◽

Protein Diets

Hepatic encephalopathy (HE) is a common neurological consequence in patients with cirrhosis and has a healthcare burden of USD 5370 to 50,120 per patient annually. HE significantly hampers the quality of life and is a major cause of morbidity and mortality. Patients with cirrhosis are at a high risk for protein-calorie malnutrition due to altered metabolism. Current evidence has changed the old belief of protein restriction in patients with cirrhosis and now 1.2 to 1.5 g/kg/day protein intake is recommended. Case series and studies with small numbers of participants showed that a vegetarian protein diet decreases the symptoms of HE when compared to a meat-based diet, but the evidence is limited and requires further larger randomized controlled trials. However, vegetable or milk-based protein diets are good substitutes for patients averse to meat intake. Branch chain amino acids (BCAA) (leucine, isoleucine and valine) have also been shown to be effective in alleviating symptoms of HE and are recommended as an alternative therapy in patients with cirrhosis for the treatment of HE. In this review, we provide an overview of current literature evaluating the role of protein intake in the management of HE in cirrhosis.

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The role of tryptophan in hepatic encephalopathy

Acta Neuropsychiatrica ◽

10.1017/s0924270800033810 ◽

1993 ◽

Vol 5 (4) ◽

pp. 71-75

Author(s):

C. Aaldijk ◽

W.W. Van Den Broek ◽

R.C. Van Der Mast

Keyword(s):

Hepatic Encephalopathy ◽

Clinical Picture ◽

Serotonergic System ◽

Pathogenetic Mechanisms ◽

Research Findings ◽

Glutamine Synthesis ◽

The Brain ◽

Tryptophan Uptake

SummaryIn this review the most important hypotheses for the occurrence of the clinical picture of hepatic encephalopathy are discussed. As possible pathogenetic mechanisms are raised: dysfunction of the serotonergic system due to an increased tryptophan uptake in the brain, an elevated intracerebral ammoniac concentration and glutamine synthesis, and a heightened intracerebral GABA-activity.The dysregulation of the serotonergic system as a consequence of the increased intracerebral tryptophan uptake is described as one of the most important pathogenetic mechanisms. The elevated intracerebral ammoniac concentration and the elevated intracerebral glutamine synthesis play in this a facilitating role. The similarity in symptomatology of the clinical picture of HE and the serotonergic syndrome support this hypothesis. Due to contradictory research findings the role of the GABA-ergic system and the occurrence of HE remains unclear.

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