Peripheral nerve injuries (PNIs) present a significant clinical challenge due to the inherently limited regenerative capacity of the adult nervous system. Conventional therapeutic strategies, such as nerve autografting and systemic pharmacological interventions, are often limited by donor site morbidity, restricted graft availability, and suboptimal drug bioavailability. In this context, gelatin-based hydrogels have emerged as a promising class of biomaterials due to their excellent biocompatibility, biodegradability, and structural similarity to the native extracellular matrix. These hydrogels could offer a highly tunable platform capable of supporting cellular adhesion, promoting axonal elongation, and enabling localized and sustained release of therapeutic agents. This narrative review synthesizes recent advances in the application of gelatin-based hydrogels for peripheral nerve regeneration, with a particular focus on their use as delivery vehicles for neurotrophic factors, stem cells, and pharmacologically active compounds. Additionally, this review provides a foundation for extending our ongoing preclinical study, evaluating the neuroregenerative effects of alpha-lipoic acid, B-complex vitamins, and a deproteinized hemoderivative in a murine PNI model. Although systemic administration has demonstrated promising neuroprotective effects, limitations related to local drug availability and off-target exposure highlight the need for site-specific delivery strategies. In this regard, gelatin hydrogels might represent an excellent candidate for localized, controlled drug delivery. The review concludes by discussing formulation techniques, manufacturing considerations, biological performance, and key translational and regulatory aspects.

Background: Anxiety disorders are prevalent mental health conditions often accompanied by various comorbidities. The association between anxiety and liver disease, as well as fluctuations in blood sugar levels, highlights the importance of carefully evaluating patients with anxiety undergoing antidepressant therapy. The aim of this study was to conduct a comparative assessment of liver function and blood glucose levels in patients diagnosed with anxiety disorders while considering potential gender-specific differences. Methods: An analysis was conducted over a 24-month period. This study included 88 patients diagnosed with anxiety disorders, with symptoms severe enough to require hospitalization, aged 18 or older, undergoing antidepressant monotherapy, without any additional pathologies. Liver enzymes (AST, ALT, GGT), AST/ALT ratio, and blood glucose levels were measured and compared. Results: While no significant differences were found between antidepressant classes, increased GGT levels were observed in men older than 40 years compared to women of the same age, suggesting that alcohol consumption may be a coping mechanism for anxiety. This gender difference was not observed among young patients. Conclusions: Early detection of alcohol consumption is essential in patients with anxiety disorders in order to prevent alcohol-related liver damage and to adjust the management of both conditions accordingly.

Background: While depression can be associated with multiple comorbidities, the association between depression and liver injury significantly increases the mortality risk. The aim of this study was to evaluate if moderate alcohol intake affects the rate of clinical relapses in patients treated with antidepressants as monotherapy. Methods: We assessed, over a period of 30 months, the clinical records of 254 patients with depressive disorder, of either gender, without additional pathologies, receiving monotherapy treatment with antidepressants. Thirty-three patients with alcohol abuse, alcoholism or significant cognitive impairment were excluded. The medical and psychiatric history, medication and liver enzyme values were collected and analyzed. Results: Out of the 221 patients who met the inclusion criteria, 78 experienced relapses of depression. The rate of relapse did not correlate with the levels of liver enzymes. Alcohol consumption, as objectified based on GGT levels and the AST/ALT ratio, suggested that men had higher alcohol intake compared to women. Patients treated with serotonin-norepinephrine reuptake inhibitors (SNRIs) with elevated AST levels were approximately 9 times more likely to relapse, while the ones with elevated GGT had a 5.34 times higher risk. While GGT levels remained a marker for relapse in men with elevated GGT, ALT and not AST proved to be a better risk indicator for relapses in male patients. Conclusion: The use of SNRIs in depressed male patients with moderate alcohol intake should be carefully considered, as they might be susceptible to higher risks of relapse compared to alternative antidepressant therapies.

The treatment of acute life-threatening events in patients suffering from chronic pathologies is problematic, as physicians need to consider multisystemic drug effects. Regarding Cerebrolysin, a Sonic Hedgehog signaling pathway amplifier and one of the few approved neurotrophic treatments for stroke patients, concerns of excessive Hedgehog pathway activation that could accelerate NAFLD progression to cirrhosis seem valid. We investigated stroke patients treated with Cerebrolysin that presented elevated levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). We also investigated the efficiency of Cerebrolysin in reversing the neurogenesis inhibition within the hippocampus in a mouse model of NAFLD by evaluating behavior and histological outcomes. NeuN, BrdU and Iba1 positive signals in the cortex and hippocampus of the animals were also observed. Clinically, Cerebrolysin improved AST levels in a majority of stroke patients with hepatic damage. The same treatment in an experimental setup was able to reverse anxiety-like behavior in MCD mice, reducing their freezing time from 333.61 ± 21.81 s in MCD animals to 229.17 ± 26.28 in treated ones. The use of Cerebrolysin did not improve short-term memory nor rescued cell multiplication in the hippocampus after MCD food intake. Understanding the neuroprotective and neurotrophic effects that drugs have on NAFLD patients can significantly contribute to a suitable therapeutic approach.

Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment in a murine model of depression and liver damage, considering age-related differences. Young and aged male C57BL/6N mice were submitted to chronic unpredictable mild stress (CUMS) and methionine–choline-deficient (MCD) diet to induce depressive-like behavior and NAFLD. Behavioral testing (sucrose preference test, open field test, novel object recognition test, Crawley’s sociability test) were used to assess ketamine’s (50 mg/kg) effect on behavior. Hepatic ultrasonography was utilized to evaluate liver status. The cortical and hippocampal NeuN+, GFAP+, and Iba1+ signals were quantified for each animal. Ketamine administration proved effective in relieving anhedonia and anxiety-like behavior, regardless of liver damage. Although ketamine treatment did not improve memory in animals with liver damage, it enhanced sociability, particularly in aged subjects. The acute administration of ketamine did not affect the severity of liver injury, but seems to affect astrogliosis and neuronal loss. Although animal models of depression only replicate certain clinical features of the condition, they remain valuable for evaluating the complex and varied effects of ketamine. By applying such models, we could demonstrate ketamine’s therapeutic versatility, and also indicate that responses to the treatment may differ across different age groups.

Peripheral nerve injuries, particularly those involving the sciatic nerve, remain a major clinical challenge due to incomplete functional recovery and the limited translation of preclinical advances into effective therapies. This review synthesizes current evidence on the phase-specific evaluation of sciatic nerve regeneration in preclinical models, integrating behavioral, sensory, electrophysiological, and morphological approaches across the acute, subacute (Wallerian degeneration), early regenerative, and late regenerative phases. By mapping functional readouts onto the underlying biological events of each phase, we highlight how tools such as the Sciatic Functional Index, Beam Walk test, Rotarod test, nerve conduction studies, and nociceptive assays provide complementary and often non-interchangeable information about motor, sensory, and neuromuscular recovery. We further examine emerging therapeutic strategies, including intraoperative electrical stimulation, immunomodulation, platelet-rich plasma, bioengineered scaffolds, conductive and piezoelectric conduits, exosome-based hydrogels, tacrolimus delivery systems, and small molecules, emphasizing the importance of aligning their mechanisms of action with the dynamic microenvironment of peripheral nerve repair. Despite substantial advancements in experimental models, an analysis of publication trends and registries reveals a persistent translational gap, with remarkably few clinical trials relative to the high volume of preclinical studies. To illustrate how mechanistic insights can be complemented by molecular-level characterization, we also present a targeted computational analysis of alpha-lipoic acid (ALA,) including frontier orbital energies, physicochemical descriptors, and docking interactions with IL-6, TGF-β, and a growth-factor receptor—performed solely for this molecule due to its documented structural availability and relevance. By presenting an integrated, phase-specific framework for functional assessment and therapeutic evaluation, this review underscores the need for standardized, biologically aligned methodologies to improve the rigor, comparability, and clinical relevance of future studies in sciatic nerve regeneration.