Obesity, designated by the World Health Organization (WHO) as the "21st-century emerging infectious disease," affects one billion individuals worldwide. Recent scientific breakthroughs offer hope for a revolutionary approach to weight management and neurological disorders. Researchers have identified key mechanisms in the brain that regulate fat metabolism and are developing innovative treatments, including the drug KDS2010.
The Brain's Role in Weight Regulation
The hypothalamus, located in the brain, plays a crucial role in overseeing the complex balance between food intake and energy expenditure. Neurons in the lateral hypothalamus are connected to fat tissue and involved in fat metabolism, but their exact role in fat metabolism regulation has remained a mystery until now.
Researchers discovered a cluster of neurons in the hypothalamus that specifically express the receptor for the inhibitory neurotransmitter GABA (Gamma-Aminobutyric Acid). This cluster, associated with the α5 subunit of the GABAA receptor, was named the GABRA5 cluster.
In a diet-induced obese mouse model, researchers observed significant slowing in the pacemaker firing of the GABRA5 neurons. Inhibiting the activity of these GABRA5 neurons using chemogenetic methods led to a reduction in heat production (energy consumption) in brown fat tissue, resulting in fat accumulation and weight gain. Conversely, when the GABRA5 neurons in the hypothalamus were activated, the mice achieved successful weight reduction, suggesting that the GABRA5 neurons may act as a switch for weight regulation.
Astrocytes: Key Regulators of GABRA5 Neuron Activity
In a surprising turn of events, the research team discovered that astrocytes in the lateral hypothalamus regulate the activity of the GABRA5 neurons. Astrocytes, star-shaped non-neuronal cells in the brain, react to disease and injury by releasing chemicals to help protect neurons from damage. The numbers and sizes of the reactive astrocytes are increased, and they begin to overexpress the MAO-B enzyme (Monoamine Oxidase B).
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MAO-B plays a crucial role in the metabolism of neurotransmitters in the nervous system and is more predominantly expressed in reactive astrocytes. This leads to the production of a large amount of tonic GABA, which inhibits the surrounding GABRA5 neurons.
Suppressing the expression of the MAO-B gene in reactive astrocytes can decrease GABA secretion, thereby reversing the undesirable inhibition of the GABRA5 neurons. Using this approach, the researchers increased the heat production in the fat tissue of the obese mice, allowing them to achieve weight loss even while consuming a high-calorie diet. This experimentally proves that the MAO-B enzyme in reactive astrocytes can be an effective target for obesity treatment without compromising appetite.
Reactive astrocytes express a high level of MAOB and release a high level of GABA, which results in the inhibition of GABRA5 neurons, decreasing thermogenesis in brown fat tissues and increasing white fat storage. Restoring GABRA5 neuron activity increases brown fat thermogenesis and decreases white fat storage.
KDS2010: A Selective MAO-B Inhibitor
KDS2010, a selective and reversible MAO-B inhibitor, was transferred to a biotech company Neurobiogen in 2019 and is currently undergoing Phase 1 clinical trials. When tested on an obese mouse model, the drug yielded remarkable results, demonstrating a substantial reduction in fat accumulation and weight without any impacts on the amount of food intake. KDS2010 treatment increased fat tissue metabolism and decreased fat storage in obese mice fed a high-fat diet, without impacting the amount of food they ate.
Postdoctoral researcher SA Moonsun said, "Previous obesity treatments targeting the hypothalamus mainly focused on neuronal mechanisms related to appetite regulation." She added, "To overcome this, we focused on the non-neuronal 'astrocytes' and identified that reactive astrocytes are the cause of obesity."
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KDS2010 for Neuropathic Pain
Monoamine oxidase (MAO) inhibitors have been investigated for the treatment of neuropathic pain. Studies assessing the antiallodynic effects of KDS2010, a novel MAO-B inhibitor, on paclitaxel (PTX)-induced mechanical hypersensitivity have shown promising results.
Oral administration of KDS2010 effectively relieved PTX-induced mechanical hypersensitivity in a dose-dependent manner. KDS2010 (25 mg/Kg) significantly prevented and suppressed PTX-induced pain responses with minimal effects on the body weight, motor activity, and working memory. KDS2010 significantly reduced reactive astrocytosis and reactive oxygen species (ROS) level in the L4-L6 spinal cord of PTX-treated mice.
Furthermore, KDS2010 reversed the attenuation of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency in spinal dorsal horn neurons, although it failed to restore the reduced tonic GABAA inhibition nor the increased GABA transporter 1 (GAT1) expression in PTX-treated mice. In addition, bath application of a reactive oxygen species (ROS) scavenger (PBN) restored the sIPSC frequency in PTX-treated mice but not in control and PTX + KDS2010-treated mice. These results indicated that the antiallodynic effect of KDS2010 is not due to a MAO-B-dependent GABA production. Finally, PBN alone also exerted a similar analgesic effect as KDS2010, but a co-treatment of PBN with KDS2010 showed no additive effect, suggesting that inhibition of MAO-B-dependent ROS production is responsible for the analgesic effect by KDS2010 on PTX-induced allodynia.
KDS2010 for Parkinson's Disease
Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD). Researchers tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD.
KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates.
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MAO-B expression is dramatically elevated in reactive astrocytes and that MAO-B is responsible for astrocytic GABA synthesis through the putrescine degradation pathway. GABA from reactive astrocytes in the substantia nigra pars compacta (SNpc) tonically inhibits neighboring dopaminergic (DAergic) neurons, thereby suppressing the synthesis and release of dopamine