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Amitriptyline is a tricyclic antidepressant commonly used for depressive disorders and is prescribed off-label for several neurological conditions like neuropathic pain, migraines and anxiety. Besides their action on the reuptake of monoaminergic neurotransmitters, tricyclic antidepressants interact with several additional targets that may contribute to either therapeutic or adverse effects. Here, we investigated the effects of amitriptyline on proliferation and autophagy (i.e., an evolutionarily conserved catabolic pathway responsible for the degradation and recycling of cytoplasmic material) in human SH-SY5Y neuroblastoma cell cultures. The dose and time-dependent upregulation of the autophagy marker LC3II and the autophagy receptor p62, with the accumulation of LAMP1 positive compartments, were observed in SH-SY5Y cells exposed to the amitriptyline. These effects were accompanied by reduced cell viability and decreased clonogenic capacity, without a significant induction of apoptosis. Decrease viability and clonogenic activity were still observed in autophagy deficient Atg5−/− MEF and following pre-treatment of SH-SY5Y culture with the autophagy inhibitor chloroquine, suggesting that they were independent from autophagy modulation. Our findings demonstrate that amitriptyline acts on pathways crucial for cell and tissue homeostasis (i.e., autophagy and proliferation) and pose the basis for further studies on the potential therapeutic application of amitriptyline, as well as the consequences of its use for long-term treatments. [ABSTRACT FROM AUTHOR]

Background: According to scientific literature, some 99% of patients affected by Alzheimer's disease (AD) suffer from behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms (NPSs). In particular, agitation is one of the most difficult disorders to treat. States of agitation represent a very serious problem as they make these subjects dangerous for themselves and others and worsen as the disease advances. To date, there are no specific solutions for treating agitation. The only authorized drug is risperidone (as well as brexpiprazole, approved by the FDA on 11 May 2023), which can be used for no longer than 6–12 weeks because it increases the risk of death—owing to cardiocerebrovascular accidents—by 1.6–1.7 times. Methods: In order to address the latter noteworthy unmet medical need, NanoBEO was produced. The aim of the present work is to generate the health technology assessment (HTA) of this nanotechnological device. The latter consists of a controlled release system, based on solid lipid nanoparticles loaded with bergamot essential oil (BEO). Results: The results of the present research assessed the current evidence in the field of non-pharmacological treatments for this condition, including relevant primary preclinical and clinical data studies supporting the use of this device and the production of the operative plan for its launch on the market. The findings offer recommendations for decision-making on its implementation in dementia. Conclusions: NanoBEO represents a public-worth innovation in this neglected area, marking a significant advancement in the history of dementia, moving from academic research to product development. [ABSTRACT FROM AUTHOR]

Background: An estimated 57.4 million people live with dementia worldwide, with the social burden of the disease steadily growing. Despite the approval of lecanemab and ongoing trials, there is still a lack of effective and safe treatments for behavioral and psychological symptoms of dementia (BPSD), which affect 99% of patients. Agitation is one of the most disabling BPSD, with a crosssectional prevalence of =50% in nursing homes, and refers to help-seeking behavior in response to various sources of discomfort, among which pain is a crucial component. Methods: This pilot phase of the BRAINAID (NCT04321889) trial aimed to assess the effectiveness of the patented nanotechnological device NanoBEO in older (=65 years) people with severe dementia. This randomized placebo-controlled trial, with quadruple masking that involved all operators and participants, followed the SPIRIT and CONSORT statements. A total of 29 patients completed the trial. The patients were randomly allocated in a 1:1 ratio to the NanoBEO or placebo group, and the corresponding product was applied on both arms once daily for 4 weeks, with a 4-week follow-up period. The primary endpoint was efficacy against agitation. The secondary endpoints were efficacy against agitation at follow-up and efficacy against pain. Any adverse events were reported, and biochemical analyses were performed. Results: The NanoBEO intervention reduced the frequency (28%) and level of disruptiveness of agitated behaviors. The effect on frequency was statistically significant after 2 weeks of treatment. The efficacy of NanoBEO on agitated behaviors lasted for the entire 4-week treatment period. No additional psychotropic drugs were prescribed throughout the study duration. The results after 1 week of treatment demonstrated that NanoBEO had statistically significant analgesic efficacy (45.46% improvement in pain intensity). The treatment was well tolerated. Discussion: This trial investigated the efficacy of NanoBEO therapy in managing agitation and pain in dementia. No need for rescue medications was recorded, strengthening the efficacy of NanoBEO in prolonged therapy for advanced-stage dementia and the usefulness of the intervention in the deprescription of potentially harmful drugs. This study provided a robust rationale for the application of NanoBEO in a subsequent large-scale pivotal trial to allow clinical translation of the product. [ABSTRACT FROM AUTHOR]

A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn. [ABSTRACT FROM AUTHOR]