Medical hypotheses最新文献

Potential role of microalgae in delaying early menarche in girls with central precocious puberty 微藻延缓中枢性性早熟女孩月经初潮的潜在作用

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-18 DOI: 10.1016/j.mehy.2026.111917

Monica Gulati , Bhupinder Kapoor , Maritza Guerrero , Dina Keumala Sari , Gayani Imanthika Dias , Ivan Salazar Chang , Sachin Kumar Singh

Central precocious puberty (CPP) in girls is characterized by an early onset of puberty. Premature thelarche occurring before age of 8 years in such cases is followed by onset of menarche in next 2–3 years. Though certain causative environmental, genetic and hormonal factors have been identified, the exact etiology remains largely elusive in many cases. A connection between gut microbiome (GM) and precocious puberty has been widely reported attributing it to the well-known gut-endocrine axis. Gut dysbiosis has been proposed as the “missing link” in idiopathic CPP (ICPP). Accordingly, biotherapeutic strategies such as probiotic therapy, fecal microbiota transplantation, and dietary interventions (e.g. phytoestrogens and polyphenols) have been successfully tried. Recent studies have identified microalgae as a sustainable source of high-quality protein, with a number of additional benefits. These are attributed to their demonstrated anti-inflammatory, antioxidant, and anticancer properties. Moreover, microalgae are widely reported to restore gut microbiome homeostasis by exerting dual probiotic and prebiotic functions and influencing sex hormone biotransformation. Their role in biotransformation of sex hormones, therefore, makes microalgae a suitable candidate for this role per se. By joining the pieces of these intricate clues, we hypothesize that inclusion of microalgae in diet represents future of nutritional interventions in ICPP. Recognition of ICPP by onset of thelarche will alert the parents, physicians and nutritionists. Inclusion of nutritional supplementation with microalgae after this, could offer a rational approach for delaying the oncoming onset of menarche in children with ICPP.

中枢性性早熟（CPP）在女孩的特点是早熟。在这种情况下，在8岁之前发生的过早月经初潮在接下来的2-3年内开始。虽然已经确定了某些环境、遗传和激素的致病因素，但在许多情况下，确切的病因仍然难以捉摸。肠道微生物组（GM）与性早熟之间的联系已被广泛报道，将其归因于众所周知的肠道内分泌轴。肠道生态失调被认为是特发性CPP （ICPP）的“缺失环节”。因此，诸如益生菌治疗、粪便微生物群移植和饮食干预（如植物雌激素和多酚）等生物治疗策略已被成功尝试。最近的研究已经确定微藻是高质量蛋白质的可持续来源，具有许多额外的好处。这是由于它们具有抗炎、抗氧化和抗癌的特性。此外，微藻被广泛报道通过发挥益生菌和益生元的双重功能以及影响性激素的生物转化来恢复肠道微生物群的稳态。因此，它们在性激素生物转化中的作用使微藻本身成为这一作用的合适候选者。通过将这些错综复杂的线索结合起来，我们假设在饮食中加入微藻代表了ICPP营养干预的未来。在发病时对ICPP的认识将提醒家长、医生和营养学家。在此之后加入微藻营养补充剂，可以为延迟ICPP患儿初潮的到来提供一种合理的方法。

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引用次数: 0

Osteoclasts may play key roles in initiating vascular calcification during atherosclerosis 破骨细胞可能在动脉粥样硬化期间启动血管钙化中起关键作用

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-24 DOI: 10.1016/j.mehy.2026.111928

Yuxiao Liu , Jingqi Wu , Jingrong Chen , Hongmei Zhang , Mingzheng Li

Vascular calcification, characterized by the ectopic deposition of calcium and phosphate crystals or even bone-like tissue, is a major risk factor for cardiovascular diseases such as atherosclerosis. However, the explicit mechanism remains unsettled. Current research demonstrates that atherosclerotic vascular calcification is a form of extraskeletal ossification—an active, cell-mediated process that closely resembles bone from macroscopic features down to the nanoscale structure. The mechanism underlying atherosclerotic calcification may be remarkably similar to those regulating bone remodeling and biomaterials-induced heterotopic ossification. This similarity is notably evidenced by the presence of osteoclast-like cells within vascular plaques. Based on previous findings that osteoclasts play key roles in initiating biomaterial-induced heterotopic ossification, we hypothesize for the first time that osteoclasts formed within the vascular wall may act as an ‘initiating signal’ triggering the development of atherosclerotic vascular calcification. This perspective may open new avenues for research into atherosclerotic calcification and contribute to the future development of strategies for its prevention and treatment.

血管钙化以钙和磷酸盐晶体甚至骨样组织的异位沉积为特征，是动脉粥样硬化等心血管疾病的主要危险因素。然而，明确的机制仍未解决。目前的研究表明，动脉粥样硬化性血管钙化是骨骼外骨化的一种形式——一种活跃的、细胞介导的过程，从宏观特征到纳米级结构都与骨骼非常相似。动脉粥样硬化钙化的机制可能与调节骨重塑和生物材料诱导的异位骨化非常相似。血管斑块内存在的破骨细胞样细胞明显证明了这种相似性。基于先前的研究结果，破骨细胞在启动生物材料诱导的异位骨化中起关键作用，我们首次假设血管壁内形成的破骨细胞可能作为触发动脉粥样硬化性血管钙化发展的“启动信号”。这一观点可能为动脉粥样硬化性钙化的研究开辟新的途径，并有助于未来预防和治疗策略的发展。

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引用次数: 0

Myocardial cell-derived exosomal miR-155-5p promotes depressive disorders in CVD via microglial SIRT1 pathway 心肌细胞源性外泌体miR-155-5p通过小胶质SIRT1途径促进CVD抑郁症

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-14 DOI: 10.1016/j.mehy.2026.111906

Meng Ning , Zhibin Zhang , Chenguang Zheng

Patients with cardiovascular disease (CVD) commonly experience comorbid depression; however, the mechanistic pathways linking cardiac pathology to depressive symptoms remain poorly elucidated. Here, we propose a novel hypothesis: myocardial injury induces cardiomyocytes to secrete exosomes enriched in miR-155-5p. We posit that these cardiogenic exosomes can cross the blood–brain barrier, be selectively taken up by microglia, and subsequently suppress Sirtuin 1 (SIRT1) expression in these cells. SIRT1 downregulation may trigger microglial activation, promote neuroinflammation, and thereby contribute to the onset of depressive-like behaviors. This hypothesis is grounded in convergent lines of evidence: (i) miR-155-5p is consistently upregulated in both CVD patients and individuals with depression; (ii) bioinformatic analyses robustly predict SIRT1 as a direct, functionally relevant target of miR-155-5p; and (iii) preclinical studies demonstrate amelioration of depressive-like phenotypes following either inhibition of miR-155-5p or pharmacological activation of SIRT1. If experimentally validated, this exosome-mediated heart–brain axis would offer a mechanistically coherent framework for understanding CVD–depression comorbidity—and identify miR-155-5p and SIRT1 as promising candidates for diagnostic biomarkers and targeted interventions.

心血管疾病（CVD）患者通常会经历共病性抑郁症；然而，将心脏病理与抑郁症状联系起来的机制途径仍不清楚。在这里，我们提出了一个新的假设：心肌损伤诱导心肌细胞分泌富集miR-155-5p的外泌体。我们假设这些心源性外泌体可以穿过血脑屏障，被小胶质细胞选择性地吸收，随后抑制这些细胞中Sirtuin 1 （SIRT1）的表达。SIRT1下调可能触发小胶质细胞激活，促进神经炎症，从而导致抑郁样行为的发生。这一假设是基于趋同的证据线：(i) miR-155-5p在心血管疾病患者和抑郁症患者中持续上调；（ii）生物信息学分析强有力地预测SIRT1是miR-155-5p的直接、功能相关的靶标；（iii）临床前研究表明，抑制miR-155-5p或药理激活SIRT1后，抑郁样表型得到改善。如果实验验证，这种外泌体介导的心脑轴将为理解cvd -抑郁症合并症提供一个机制上一致的框架，并将miR-155-5p和SIRT1确定为诊断生物标志物和靶向干预的有希望的候选者。

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引用次数: 0

A novel strategy combining high-intensity interval training and exogenous ketone supplementation for obesity treatment 结合高强度间歇训练和外源性酮补充治疗肥胖的新策略

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-23 DOI: 10.1016/j.mehy.2026.111925

Jay Lee , Zhaowei Kong , Jinlei Nie

High-intensity interval training (HIIT) and exogenous ketone supplementation (EKS) have individually demonstrated potential in addressing overweight and obesity, particularly through their effects on appetite regulation and dietary behavior. However, the therapeutic potential of EKS in obesity management remains underexplored, and how it interacts with HIIT remains unclear. We hypothesize that combining HIIT and EKS may have a synergistic effect through “Neurocognitive-Behavioral Mechanisms”. These mechanisms include direct effects on appetite-related brain pathways and indirect effects such as improvements in cognitive function that support healthier eating habits. Both HIIT and EKS may also increase levels of newly identified signaling compounds, such as lactate-phenylanine (Lac-Phe) and 3-β-hydroxybutyrate (BHB)-Phe, which have been linked to reduced food intake in animal studies. Importantly, the shared pathways through which HIIT and ketones enhance cognitive function suggest that future obesity treatments could focus on optimizing brain and metabolic health, rather than relying solely on calorie restriction, to improve long-term adherence. Further research should clarify the neurocognitive and metabolic pathways involved and examine the long-term impact of combined HIIT and EKS interventions. This conceptual framework offers a novel perspective on how brain and behavior interact in obesity and may guide the development of innovative lifestyle strategies.

高强度间歇训练（HIIT）和外源性酮补充剂（EKS）分别证明了解决超重和肥胖的潜力，特别是通过它们对食欲调节和饮食行为的影响。然而，EKS在肥胖管理中的治疗潜力仍未得到充分探索，其如何与HIIT相互作用仍不清楚。我们假设HIIT和EKS结合可能通过“神经认知-行为机制”产生协同效应。这些机制包括对食欲相关的大脑通路的直接影响和间接影响，如改善支持健康饮食习惯的认知功能。HIIT和EKS也可能增加新发现的信号化合物的水平，如乳酸-苯胺（Lac-Phe）和3-β-羟基丁酸(BHB)-Phe，在动物研究中，它们与减少食物摄入量有关。重要的是，HIIT和酮类增强认知功能的共同途径表明，未来的肥胖治疗可以专注于优化大脑和代谢健康，而不是仅仅依靠卡路里限制，以提高长期依从性。进一步的研究应阐明所涉及的神经认知和代谢途径，并检查HIIT和EKS联合干预的长期影响。这一概念框架为大脑和行为如何在肥胖中相互作用提供了一个新的视角，并可能指导创新生活方式策略的发展。

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引用次数: 0

The mechanical protector paradox: a hypothesis linking transition zone enlargement, urethral angle, and carcinogenesis via intraprostatic reflux 机械保护器悖论：一个连接过渡区扩大、尿道角度和前列腺内反流致癌的假说

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-23 DOI: 10.1016/j.mehy.2026.111922

Yu-Hsiang Lin , Po-Ting Lin , Tzu-Chi Teng , Yu-Ting Chen , Chen-Pang Hou , Jau-Yuan Chen , Chien-Lun Chen

The relationship between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains paradoxical: both share inflammatory pathways, yet larger prostates often harbor less aggressive disease. This paradox may be explained by the mechanical interaction between the transition zone (TZ) and the peripheral zone (PZ). We hypothesize that urethral morphology, particularly a more acute prostatic urethral angle (PUA), acts as a primary biomechanical risk factor. A sharper urethral bend increases local hydrodynamic pressure and reflux potential, promoting the pro-inflammatory stimuli in the PZ. Conversely, we propose that progressive TZ enlargement acts as a “mechanical protector” against this insult. By compressing the PZ, the enlarging TZ narrows its ducts and reduces the intraprostatic reflux driven by the PUA. This effect attenuates the inflammatory microenvironment that drives malignant transformation. Integrating these factors, we propose a mechanical–inflammatory model in which prostate volume and urethral geometry jointly regulate intraprostatic inflammation. Integrating these factors, we propose a mechanical–inflammatory model in which prostate volume and urethral geometry jointly regulate intraprostatic inflammation. This hypothesis provides a unifying explanation for the inverse association between prostate size and cancer aggressiveness and suggests new imaging and mechanistic pathways for future investigations.

良性前列腺增生（BPH）和前列腺癌（PCa）之间的关系仍然是矛盾的：两者都有共同的炎症途径，但较大的前列腺往往具有较小的侵袭性疾病。这种矛盾可以用过渡区（TZ）和外围区（PZ）之间的力学相互作用来解释。我们假设尿道形态，特别是前列腺尿道角（PUA），是主要的生物力学危险因素。更尖锐的尿道弯曲增加了局部流体动力压力和反流电位，促进了PZ的促炎刺激。相反，我们建议渐进式TZ扩大作为对抗这种侮辱的“机械保护器”。通过压缩PZ，增大的TZ变窄其导管并减少由PUA驱动的前列腺内反流。这种作用减弱了驱动恶性转化的炎症微环境。综合这些因素，我们提出了一个机械炎症模型，其中前列腺体积和尿道几何形状共同调节前列腺内炎症。综合这些因素，我们提出了一个机械炎症模型，其中前列腺体积和尿道几何形状共同调节前列腺内炎症。这一假设为前列腺大小与癌症侵袭性之间的负相关关系提供了统一的解释，并为未来的研究提供了新的成像和机制途径。

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引用次数: 0

Cell psychology: a conceptual reinterpretation of cellular stress responses through cognitive and psychological analogies 细胞心理学：通过认知和心理类比对细胞应激反应的概念重新解释

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-23 DOI: 10.1016/j.mehy.2026.111923

Nalin Gümüşçü

This hypothesis proposes that cells, much like psychological entities, display adaptive, emotion-like responses and decision-oriented behavioral patterns when confronted with internal or external stressors. Termed “cell psychology”, this framework suggests that biological stress, genomic instability, and environmental fluctuations elicit cellular reactions analogous to psychological states such as anxiety, fatigue, exhaustion, and self-preservation. Under adverse conditions, cells may adopt altruistic strategies—most notably apoptosis—to maintain tissue integrity, or shift toward narcissistic, competitive behaviors such as uncontrolled proliferation, immune evasion, and tumorigenesis. Mitochondrial dysfunction, oxidative stress, lysosomal impairment, and stress-induced epigenetic alterations represent molecular parallels of emotional collapse, maladaptation, and aging, reflecting a progressive loss of resilience and homeostatic regulation. Interpreting cellular behavior through a psychological lens offers a novel integrative perspective linking molecular biology, neuropsychology, systems biology, and artificial intelligence. Parallels between cellular decision-making networks and cognitive processes—including information processing, memory formation, pattern recognition, and threshold evaluation—indicate that core principles of adaptation may operate across multiple biological scales. Cells detect signals, integrate competing inputs, and generate context-dependent outcomes, resembling primitive forms of cognitive computation.

Within this conceptual framework, “cell psychology” provides a bottom-up model for understanding cooperation, communication failure, pathological deviation, and multicellular organization. Reframing cellular responses as rudimentary expressions of choice, memory, and strategic adaptation offers new avenues for interpreting aging, cancer progression, regenerative capacity, and emergent biological order. Ultimately, this hypothesis raises the possibility that foundational elements of cognition, resilience, and behavioral complexity may originate from the adaptive, information-processing capacities intrinsic to individual cells.

这一假说认为，细胞就像心理实体一样，在面对内部或外部压力源时表现出适应性的、类似情绪的反应和决策导向的行为模式。这一框架被称为“细胞心理学”，认为生物应激、基因组不稳定和环境波动引发细胞反应，类似于焦虑、疲劳、疲惫和自我保护等心理状态。在不利的条件下，细胞可能会采取利他主义的策略（最明显的是凋亡）来维持组织的完整性，或者转向自恋、竞争行为，如不受控制的增殖、免疫逃避和肿瘤发生。线粒体功能障碍、氧化应激、溶酶体损伤和应激诱导的表观遗传改变代表了情绪崩溃、适应不良和衰老的分子相似之处，反映了恢复力和稳态调节的逐渐丧失。从心理学角度解释细胞行为提供了一种连接分子生物学、神经心理学、系统生物学和人工智能的全新综合视角。细胞决策网络和认知过程（包括信息处理、记忆形成、模式识别和阈值评估）之间的相似之处表明，适应的核心原则可能在多个生物尺度上起作用。细胞检测信号，整合竞争输入，并产生情境依赖的结果，类似于原始形式的认知计算。在这个概念框架内，“细胞心理学”为理解合作、沟通失败、病理偏差和多细胞组织提供了一个自下而上的模型。将细胞反应重新定义为选择、记忆和战略适应的基本表达，为解释衰老、癌症进展、再生能力和紧急生物秩序提供了新的途径。最终，这一假说提出了一种可能性，即认知、恢复力和行为复杂性的基本要素可能源于个体细胞固有的适应性和信息处理能力。

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引用次数: 0

3D Doppler territorial vascular mapping as a prognostic tool in uterine EMV/AVM 三维多普勒定位作为子宫EMV/AVM的预后工具

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-24 DOI: 10.1016/j.mehy.2026.111927

Amin Abolhasani Foroughi , Seyed Sina Dehghani

Acquired Uterine Enhanced Myometrial Vascularity/Arteriovenous Malformation (EMV/AVM) is uncommon vascular abnormality that can occasionally lead to severe uterine bleeding. Current Doppler indices, such as peak systolic velocity and resistance index, have limited prognostic value. We suggest that assessment of the territorial vascular supply pattern, characterized by involvement of one or multiple uterine regions (anterior, posterior, right lateral, left lateral, and fundal), using three-dimensional (3D) Doppler imaging may serve as a prognostic indicator in the management of these patients. Complex vascular architecture with multiple feeding arteries or overlapping territories may predict persistent hemorrhage and a higher need for embolization, whereas single-territory involvement may indicate a greater chance of spontaneous regression. Incorporating 3D Doppler into diagnostic protocols could refine risk stratification, reduce unnecessary interventions, and ultimately improve reproductive outcomes. This hypothesis calls for observational studies integrating vascular territory mapping alongside current Doppler parameters to establish its predictive role in acquired EMV/AVM.

获得性子宫肌层血管增强/动静脉畸形（EMV/AVM）是一种罕见的血管异常，偶尔会导致严重的子宫出血。目前的多普勒指标，如峰值收缩速度和阻力指数，对预后的价值有限。我们建议使用三维（3D）多普勒成像评估以累及一个或多个子宫区域（前、后、右侧、左侧和子宫底）为特征的领土血管供应模式，可作为这些患者治疗的预后指标。有多个供血动脉或重叠区域的复杂血管结构可能预示持续出血和更高的栓塞需求，而单一区域的累及可能表明更大的自发性消退机会。将3D多普勒纳入诊断方案可以细化风险分层，减少不必要的干预，最终改善生殖结果。这一假设需要观察性研究，结合血管区域测绘和当前多普勒参数，以确定其在获得性EMV/AVM中的预测作用。

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引用次数: 0

Post-menopause cardiovascular risk – lack of hormones or bleeding? – Increased blood viscosity due to cessation in menstrual bleeding 绝经后心血管风险-缺乏激素或出血？-由于月经停止出血，血液粘度增加

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-14 DOI: 10.1016/j.mehy.2026.111915

Erik Finlayson

引用次数: 0

From cellular cognition to psychopathology: a three-level framework of biological decision-making 从细胞认知到精神病理学：生物决策的三层框架

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-14 DOI: 10.1016/j.mehy.2026.111914

Gastón Lenin Nole Guerrero

This article proposes a three-level framework for understanding biological decision-making. At Level 1, the cellular living system perceives its environment through metabolic signals and selects adaptive states within gene regulatory networks. At Level 2, the neuron—as an evolved living system—amplifies these capacities through adaptive dendritic processing; we propose that nervous system evolution follows a hierarchical principle where newer structures acquire regulatory control over older ones. At Level 3, neuronal groups operate as collective selection units whose behavior depends on the balance between subcortical driver circuits and cortical inhibitory circuits.

The central contribution is a framework with falsifiable predictions. Cortical inhibitory control may critically depend on two energetically demanding neuronal populations: fast-spiking parvalbumin-positive interneurons (PV + ) and prefrontal pyramidal neurons (PrN). We propose that these populations share convergent vulnerability. PV + interneurons require maintenance of ionic gradients and sustained high-frequency firing. Prefrontal pyramidal neurons appear to have evolved with a specialization toward lipid metabolism, consistent with TKTL1-linked findings; they also exhibit higher energy costs due to partial myelination, depend on external lipid supply whose relevance has been highlighted by brain lipidomics studies, and show preferential enrichment of the MCT2 transporter, which could be compatible with preferential use of monocarboxylates as physiological substrate.

Critically, the type of energy substrate—not just its quantity—may determine neuronal firing stability. Metabolic studies suggest that β-hydroxybutyrate is an efficient substrate for GABA synthesis in cultured GABAergic neurons, and that ketones may favor inhibitory firing patterns while glucose may favor excitatory patterns. When the living system cannot sustain inhibitory tone, subcortical circuits such as the nucleus accumbens may assume behavioral control, restricting behavior outside conscious control and generating self-maintained pathological patterns: hyperphagia, depressive rumination, compulsion, craving.

本文提出了一个理解生物决策的三级框架。在1级，细胞生命系统通过代谢信号感知环境，并在基因调控网络中选择适应状态。在第2级，神经元——作为一个进化的生命系统——通过适应性树突处理增强了这些能力；我们提出神经系统进化遵循一个等级原则，即新结构获得对旧结构的调节控制。在第3级，神经元群作为集体选择单位运作，其行为取决于皮层下驱动回路和皮层抑制回路之间的平衡。其核心贡献是一个具有可证伪预测的框架。皮质抑制控制可能主要依赖于两个能量需求旺盛的神经元群：快速尖峰小蛋白阳性中间神经元（PV +）和前额叶锥体神经元（PrN）。我们认为这些群体具有趋同的脆弱性。PV +中间神经元需要维持离子梯度和持续的高频放电。与tktl1相关的研究结果一致，前额叶锥体神经元似乎已经进化为脂质代谢的专门化；由于部分髓鞘形成，它们还表现出更高的能量消耗，依赖于外部脂质供应，其相关性已被脑脂质组学研究强调，并表现出MCT2转运体的优先富集，这可能与优先使用单羧酸盐作为生理底物相兼容。关键的是，能量基质的类型——而不仅仅是它的数量——可能决定神经元放电的稳定性。代谢研究表明，在培养的GABA能神经元中，β-羟基丁酸盐是GABA合成的有效底物，酮类可能倾向于抑制性放电模式，而葡萄糖可能倾向于兴奋性模式。当生命系统无法维持抑制性张力时，皮层下回路（如伏隔核）可能承担行为控制，限制意识控制之外的行为，并产生自我维持的病理模式：嗜食、抑郁反刍、强迫、渴望。

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引用次数: 0

Could early-life caffeine exposure program preterm infants for later-life caffeine dependence? A mechanistic hypothesis 早期咖啡因暴露会影响早产儿日后对咖啡因的依赖吗？机械假说

IF 0.8 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2026-04-01 Epub Date: 2026-02-23 DOI: 10.1016/j.mehy.2026.111921

Çağrı Cumhur Gök , Emrah Can

Caffeine remains a primary therapeutic agent for apnea of prematurity and continues to improve respiratory stability and neurodevelopmental outcomes. Treatment occurs during a developmental window in which synaptic connectivity is rapidly expanding, receptor expression is shifting, and neuromodulatory systems are establishing long-term regulatory patterns. During this period, the maturation of A1 and A2A receptors influences neuronal excitability, sleep–wake organization, and endogenous protective mechanisms. Experimental studies demonstrate that neonatal caffeine exposure modifies A1 receptor ontogeny, alters ligand sensitivity, and induces lasting changes in ventilatory control. Considering the functional interaction between A2A and dopamine D2 receptors in striatal pathways, early adenosine antagonism may also influence the developmental calibration of reward circuitry.

Animal data consistently show that neonatal caffeine exposure produces behavioral and neuromodulatory alterations that persist into later life, affecting motor activity, sleep organization, memory performance, and responsiveness to stimulant agents. Human studies, however, have not assessed reward sensitivity, stimulant responsivity, or caffeine-use patterns in individuals born preterm, leaving an important developmental gap. These observations support a biologically grounded hypothesis: early-life caffeine therapy may shift the maturation of arousal and reward systems in ways that shape later susceptibility to altered caffeine sensitivity or reinforcement patterns. If this connection is confirmed, clinical approaches may need to reconsider dosing strategies and broaden long-term follow-up to include behavioral and neurophysiological assessments in former preterm infants treated with caffeine.

咖啡因仍然是早产儿呼吸暂停的主要治疗药物，并继续改善呼吸稳定性和神经发育结果。治疗发生在突触连接迅速扩展，受体表达转移，神经调节系统正在建立长期调节模式的发育窗口期。在此期间，A1和A2A受体的成熟影响神经元兴奋性、睡眠-觉醒组织和内源性保护机制。实验研究表明，新生儿咖啡因暴露改变了A1受体的个体发生，改变了配体的敏感性，并诱导了通气控制的持久变化。考虑到纹状体通路中A2A和多巴胺D2受体之间的功能相互作用，早期腺苷拮抗也可能影响奖励回路的发育校准。动物数据一致表明，新生儿咖啡因暴露会导致行为和神经调节的改变，这种改变会持续到以后的生活，影响运动活动、睡眠组织、记忆表现和对兴奋剂的反应。然而，人类研究还没有评估早产儿的奖励敏感性、兴奋剂反应性或咖啡因使用模式，这留下了一个重要的发展差距。这些观察结果支持了一个基于生物学的假设：生命早期的咖啡因治疗可能会改变唤醒和奖励系统的成熟，从而形成后来对改变的咖啡因敏感性或强化模式的易感性。如果这种联系得到证实，临床方法可能需要重新考虑剂量策略，并扩大长期随访，包括对接受咖啡因治疗的前早产儿的行为和神经生理评估。

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引用次数: 0