JP-2026076264-A - C-terminal fragment of tetanus toxin (HC) for the treatment of depression

Abstract

[Problem] To provide an antidepressant that has a broader range of therapeutic effects, fewer side effects, and acts more rapidly. [Solution] The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) provides therapeutic effects in motor dysfunction associated with Parkinson's disease (PD) and provides long-lasting antidepressant effects, and is therefore useful in treating and alleviating depression, particularly PD-comorbid depression. A method for treating and alleviating depression comprises administering an effective amount of the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) to a subject in need. A method for treating or alleviating motor dysfunction associated with Parkinson's disease (PD) comprises administering an effective amount of the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) to a subject in need. [Selection Diagram] None

Inventors

• ティザビ， ヨセフ

Assignees

• ハワード ユニバーシティ

Dates

Publication Date

20260511

Application Date

20260123

Priority Date

20200520

Claims (11)

1. A method for treating or alleviating depression, comprising administering an effective amount of the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) to a subject in need.
2. The method according to claim 1, wherein the depression is depression related to Parkinson's disease (PD).
3. The method according to claim 1, wherein the Hc-TeTx is administered by injection.
4. The method according to claim 1, wherein the Hc-TeTx is administered in an amount of 150 μg to 600 μg per dose.
5. The method according to claim 1, wherein the Hc-TeTx is administered in an amount of 180 μg to 540 μg per dose.
6. The method according to claim 1, wherein the Hc-TeTx increases central brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex.
7. The method according to claim 1, wherein the Hc-TeTx reduces tumor necrosis factor (TNF)-alpha (TNF-alpha) in the hippocampus and prefrontal cortex.
8. A method for treating or alleviating motor dysfunction associated with Parkinson's disease (PD), comprising administering an effective amount of the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) to a subject in need.
9. The method according to claim 8, wherein the Hc-TeTx is administered by injection.
10. The method according to claim 8, wherein the Hc-TeTx is administered in an amount of 150 μg to 600 μg.
11. The method according to claim 8, wherein the Hc-TeTx is administered in an amount of 180 μg to 540 μg.

Description

(Statement concerning research or development supported by the federal government) Some aspects of the present invention were made under grant NIH/NIAAA R03AA022479, awarded by the National Institutes, and therefore the government has certain rights in some aspects of the present invention. This method relates to the treatment or alleviation of depression, particularly depression-Parkinson's disease (PD) comorbidity. Specifically, it relates to a method for the treatment or alleviation of depression that includes administering the carboxyl-terminal domain of the tetanus toxin heavy chain (Hc-TeTx), any non-toxic fraction of tetanus toxin, or the coding sequence of Hc-TeTx. The compensation for clinical depression, characterized by feelings of discouragement, loss of interest in enjoyable activities, guilt, apathy, and difficulty concentrating, is a matter of considerable medical concern due to its relatively high prevalence. In the United States alone, approximately 16 million people, or 7% of adults, suffer from major depressive disorder, which may also include appetite and sleep disturbances, loss of productivity, and suicidal ideation. The actual suicide rate worldwide, estimated at 1 million, affects not only those affected but also their families and friends, and sometimes society as a whole (Non-Patent Literature 1). While our understanding of the highly complex neurobiological networks involved in mood regulation remains far from complete, it is known that depressive symptoms are diverse and vary greatly from patient to patient. Furthermore, numerous medications developed over the past 60 years, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), norepinephrine reuptake inhibitors (NRIs), and selective serotonin reuptake inhibitors (SSRIs), have provided significant relief to at least some patients (Non-Patent Literature 2). However, these drug therapies are based on the bioamine theory of depression, which assumes that a decrease in these neurotransmitters is the primary cause of the disorder, and have several major drawbacks. These include limited efficacy, slow onset of action, and various undesirable side effects, some of which can be persistent (Non-Patent Literature 3 and 4). Therefore, there is an urgent need for antidepressants with broader efficacy, fewer side effects, and a faster onset of action. In recent years, the significant contributions of neurotrophic factors and inflammatory processes to mood regulation/dysregulation have been elucidated, pointing to new approaches in the development of more effective antidepressants. In this context, several natural and synthetic compounds possessing anti-inflammatory properties and the ability to increase neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), have been proposed as potential novel antidepressants (Non-Patent Documents 5-8). However, research on the C-terminal domain of the tetanus toxin heavy chain (Hc-TeTx) as a potential antidepressant has not been conducted. P.E. Greenberg, A.A. Fournier, T. Sisitsky, et al., The economic burden of adults with major depressive disorder in the United States, (2005 and 2010) J Clin Psychiatry, 76 (2015), pp. 155-162M.R. Levinstein, B.A. Samuels, Mechanisms underlying the antidepressant response and treatment resistance, Front Behav Neurosci, 8 (2014), pp. 208A.J. Rush, Targeting treatments for depression: what can our patients tell us? Epidemiol. Psychiatr Sci, 26 (2017), pp. 37-39J. Ben-Sheetrit, D. Aizenberg, A.B. Csoka, et al., Post-SSRI sexual clinical dysfunction: characterization and preliminary assessment of contributory factors and dose-response relationship. J Clin Psychopharmacol, 35 (2015), pp. 273-278L.L. Hurley, Y. Tizabi, Neuroinflammation, neurodegeneration, and depression. Neurotox. Res, 23 (2013), pp. 131-144O. Kalejaiye, B. Getachew, C.L. Ferguson, et al., Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats. J Drug Alcohol Res, (2017), pp. 6: 236036C.N. Bodnar, J.M. Morganti, A.D. Bachstetter, Depression following a traumatic brain injury: uncovering cytokine dysregulation as a pathogenic mechanism. Neural Regen Res., 13 (2018), pp. 1693-1704R.S. Duman, BDNF, 5-HT, and anxiety: identification of a critical periadolescent developmental period. Am. J. Psychiatry, 174 (2017), pp. 1137-1139 The inventors have conducted extensive research and discovered that the C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) has antidepressant effects in animal models of depression and may be effective in treating depression, particularly depression associated with Parkinson's disease (PD). The inventors have found that Hc-TeTx results in a dose-dependent reduction in immobility scores, while not affecting open-field spontaneous motor activity (OFLA). In addition to the behavioral effects, the inventors discovered that in two regions closely related to mood regulation,