Role of Cyclooxygenase-2 Inhibitors in Animal Models of Epilepsy: A Systematic Review

Background: The presence of recurrent seizures characterizes epilepsy, which is defined as a chronic disorder of the nervous system. It has recently been suggested that COX-2 inhibitors may offer protective neurotherapeutic effects while simultaneously controlling seizures. The animal model is an important tool for assessing these interventions.

Objectives: This review assessed the literature regarding COX-2 inhibitors in animal models of epilepsy, focusing on their efficacy both in terms of seizure control and neuroprotection. As an effort to inform future research and clinical guidelines, the review collates information on known study gaps, particularly those related to standardized dosing and long-term outcomes.

Methodology: A comprehensive literature search was conducted on Google Scholar, PubMed, Scopus, and Web of Science using the following keywords: “Epilepsy,” “Seizure,” “Neuroprotection,” “Seizure Reduction,” “Inflammatory mediators,” and “COX-2 Inhibitors.” Out of 400 initially reviewed articles, 20 original research articles matched the selection criteria. These studies were conducted in animal models of epilepsy aimed at seizure reduction and neuroprotection through COX-2 inhibitors, and the articles were available in open-access full text. Restricted-access articles, review articles, clinical trials, and those with full-text unpublished data were not included. The risk of bias in the selected studies was assessed with SYRCLE’s tool.

Results: COX-2 inhibitors have been shown to decrease seizures and provide neuroprotection with varying success across many animal models. COX-2 inhibitors showed promise as neuroprotective agents, and their efficacy in seizure reduction has a considerable range. This systematic review highlights the considerable gaps concerning optimized dosage, efficacy duration, and comparative effectiveness across different epilepsy models.

Conclusion: COX-2 inhibitors demonstrated promise in seizure attenuation along with neuroprotection. There are important gaps regarding standardization of treatment protocols, evaluation of chronic impact, and mechanism understanding in different types of epilepsy models, which require focus from further study.

COX-2: Cyclooxigenase-2; EEG: Electroencephalogram; FDA: Food and Drug Administration; GABA-A: Gamma-aminobutyric acid type A receptor; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PGE2: Prostaglandins E 2; PTZ: Pentylenetetrazole; SOD: Superoxide dismutase; MDA: Malondialdehyde

Epilepsy is the 4th most common neurologic condition, characterized by hyper-synchronized neuronal activity and repeated seizures [1,2]. It is not only defined by spontaneous reoccurring seizures but it is also associated with other medical conditions (comorbidities and cognitive impairments) that can significantly impair the overall quality of life of the affected people. It has been established that there is a relationship between epilepsy and the presence of psychiatric disorders and cognitive impairments [2-4]. For developing successful therapeutic interventions, it is crucial to comprehensively understand the underlying mechanisms of epileptogenesis, as it plays a pivotal role in preventing the onset of epilepsy. About 25–50% of individuals show behavioural and cognitive deficits as a result of epileptogenesis. The hyper-excitability of the neuron plays an important role in developing neuropsychiatric disorders due to the imbalance between inhibitory and excitatory neurons [5].

Globally, a large population, approximately 50-70 million people, is suffering from this condition, and 20–30% of patients develop resistance to antiepileptic medications [6]. Epilepsy accounts for 0.75% of the total disease burden globally. The prevalence and incidence of epilepsy throughout the world are estimated to be 700/100000 individuals and 500/ 100000 individuals, respectively, and 2.4 million people are diagnosed with epilepsy each year [4]. Identifying the underlying cause of epilepsy is a crucial step for the diagnosis and management of epilepsy. A diverse set of neurological conditions in which an underlying brain disorder reduces the brain’s innate threshold for seizures, referred to as epilepsy, making the occurrence of spontaneous and recurrent seizures more likely. A recurrence risk of 60% is commonly used as a criterion for the diagnosis of epilepsy [7]. Numerous factors, including genetic, metabolic disorders, structural abnormalities, immune system dysfunction, and infections, are involved the development of epilepsy and in 50% of cases it may have an unknown etiology [7,8].

It is important to choose a suitable animal model to understand the epilepsy development and seizure progression process. Pilocarpine, Pentylenetetrazole (PTZ), and Kainic acid are commonly employed for the pharmacologic provocation of seizures [9]. The repeated sub-convulsive doses of PTZ, a non-competitive GABA-A receptor antagonist, can indeed bring forth certain neural alterations. PTZ’s capacity to inhibit glutamatergic signaling contributes to the process of epileptogenesis [5]. Both oxidative and inflammatory conditions can be triggered by PTZ, which in turn cause epilepsy and behavioral modification in rodents with associated neuropsychiatric comorbidities [10]. Repeated administration of PTZ leads to seizure intensification with each injection. Previous research supported that neuroinflammation may lead to epilepsy. Proinflammatory cytokines, leukocyte infiltration, increasing lipid peroxidation, and disrupting the blood-brain barrier are also involved in the pathophysiology of seizures [5].

In the synthesis of prostaglandins, the enzyme Cyclooxygenase (COX) plays an important role. COX-1 and COX-2 are induced by varying forms of activation in different tissues. In relation to some COX-2 overexpression associated neurological disorders like Alzheimer’s disease, epilepsy, and stroke, there is COX-2 overexpression often noted [11]. Prior investigations have identified the protective impact that COX-2 Inhibitors have in the kindling model of epilepsy. These neural COX-2 inhibitors have a potential application in the therapeutics of inflammation diseases due to their COX-2 selective inhibition. COX-2 is an inducible enzyme whose expression is enhanced during seizure activity and is responsible for the production of prostaglandins which increase neural excitability and cause damage. The use of COX-2 inhibitor has two important benefits: reduction of inflammation and seizure control. Regardless of some hopeful conclusions, there are considerable inconsistencies in the current studies conducted on COX-2 in epilepsy. Although COX-2 inhibitors show potential efficacy in epilepsy models, results are inconsistent due to a lack of rational dosage regimens and short durations of the studies. Moreover, the differences in the effectiveness of COX-2 inhibitors on generalized versus focal epilepsy models are still unexplored. This systematic review attempts to fill these gaps by analyzing available data on the use of COX-2 inhibitors for neuroprotection and seizure control in animal models of epilepsy.

Further research is essential to fully understand the role of neuroinflammation in epilepsy and its potential as a therapeutic target [6]. Currently, none of the existing anticonvulsant drugs approved by the FDA for treating epilepsy has demonstrated the ability to modify the disease itself. However, there is optimism that anti-inflammatory therapy could potentially provide benefits in modifying epilepsy [6].

Literature search

Four databases were searched thoroughly to collect and analyze data for this systematic review: Web of Science, PubMed, Scopus, and Google Scholar. In search strategy following keywords were searched: “epilepsy,” “neuroprotection,” “seizure control,” “inflammation,” and “COX-2 inhibitors.” These keywords were used to fetch the published and unpublished studies, and the search was restricted to original research studies using animal models of epilepsy. As a study protocol for systematic reviews, the Preferred Reporting Items (PRISMA) 2020 guidelines were followed as the study protocol. The data were compiled, and duplicates were removed using EndNote, and then titles and abstracts were screened thoroughly. To evaluate the relevance and eligibility of the articles related to the topic, articles that were selected after initial screening an extensive screening that included reading the full text of the selected articles (Figure 1).

Figure 1: PRISMA flow diagram of study selection process.

Selection of study: The following criteria were applied for study selection

• Inclusion criteria

• Utilization of animal models for epilepsy
• Focus on seizure reduction and neuroprotection 
• Use of COX-2 Inhibitors as a major therapeutic approach
• Availability of full text and open access articles
• Use the original research (No Meta-Analysis or reviews)

• Exclusion criteria

• Clinical investigations or Human trials
• Open access restrictions
• Non-availability of full text
• Meta-analysis and review articles

From the data base search engine, a total of 450 articles were found. In first round of screening, 50 articles were removed due to duplication by using endnote software. Screening of titles abstracts, and keywords was performed by two independent reviewers. 350 articles were excluded according to above mentioned inclusion exclusion criteria. Remaining 50 articles were screened for the full text availability. Twenty were excluded on the bases of full text non- availability. After in-depth analysis. Finally, 20 articles were selected after complete screening of full text that fulfill all the requirements for selection criteria.

Extraction of data

Data were extracted from the studies that included:

• Animal model for epilepsy (like PTZ-induced, Kainate-induced, and Pilocarpine-induced epilepsy models)
• Use of COX-2 inhibitor and its dosage
• Neuroprotection and seizure reduction outcomes
• Treatment duration
• Side effects

Risk of bias assessment

A specially designed risk of bias tool called SYRCLE, which includes ten questions, was used to evaluate the quality of selected studies. This tool is developed based on the Cochrane RoB tool, but it is designed particularly for laboratory animals. This tool assesses the potential for bias in the domain like, selective outcome reporting, randomization, and allocation concealment. The study’s publications were evaluated for quality. Each question received answers with Yes (Y), No (N), and Unclear (Un). Some potential biases were found, especially in sequence generation and allocation concealment. However, overall scores showed reliable evidence. The potential biases were believed to have a less likely impact on the experiment’s outcomes [12] (Tables 1-3).

Data formulation or synthesis

A narrative review was carried out to sum up the effects of COX-2 inhibitors on seizure control and protection from neurological damage in different animal models. According to the type of epilepsy model (focal vs generalized), a subgroup assessment was performed to investigate the potential variations in effectiveness.

For this systematic review, a total of 400 articles were searched, and after applying inclusion & exclusion criteria, 20 articles were finalized for the analysis. The effectiveness of Nimesulide, Rofecoxib, Celecoxib, and NS-398 COX-2 inhibitors were evaluated in PTZ, kainite, electrical stimulation, and pilocarpine induced epileptic models. Each study had specific protocols for seizure induction and examination of different doses of cyclooxygenase-2 inhibitors. To provide an example, Jiang, et al. [13], conducted a study where they administered celecoxib at 30mg/kg using a kainate model of epilepsy induction and concluded celecoxib was effective in mitigating seizures through neuroprotective mechanisms.

In the second study, using the pilocarpine-induced model, NS-398 was administered at 10 mg/kg and it was concluded that it had moderate effects on seizure reduction and neuroprotection. In the third study, Rofecoxib was administered at 15 mg/kg in the kindling model to evaluate its effects, concluding that it showed moderate effects both in neuroprotection and seizure reduction as well. Most studies, including study 4, study 6, and study 9, established that higher dosages (20-30 mg/kg) of COX-2 inhibitors produce better outcomes for neuroprotection and seizure reduction. Furthermore, emphasizing the importance of dosage optimization, some epilepsy models (such as the PTZ-induced model) using a low dosage exhibited less effectiveness.

Subgroup analysis

The effectiveness of COX-2 inhibitors in focal epilepsy models, like kainite-induced, pilocarpine-induced models) was higher than in the generalized epilepsy models, including the PTZ-induced epilepsy model. For example, celecoxib produces better results in kainite and pilocarpine induced epilepsy models in reducing seizures and providing neuroprotection in many studies (study 4, study 6, and study 18 [13]. On the other hand, PTZ-induced models demonstrated moderate effectiveness of COX-2 inhibitors on seizure reduction and neuroprotection, as in the table (studies 5, 9, and 17).

Neuroprotective effects in the selected studies were evaluated using various techniques to estimate the reduction in neurological degradation, neuroinflammation, and oxidative stress across different models of brain injury and epilepsy. A study conducted by Gopez JJ, et al. [21] in a rat traumatic brain injury model treated with DFU measured neuroprotection by assessing cyclooxygenase-2 expression, caspase-3 activation (a marker of apoptosis), and improvements in neuronal functions. The study concluded that DFU significantly reduced neuronal apoptosis and neuroinflammation [15]. Jiang used an EP2 receptor antagonist (TG6-10-1) to evaluate neuroprotective effects in a pilocarpine-induced status epilepticus model in mice. These effects included reduced levels of cytokines, gliosis, and maintenance of blood-brain barriers, as well as decreased neurological degradation in the hippocampus [16].

A study [22] revealed that disruption of blood blood-brain barrier and neurological damages were significantly reduced as the level of COX-2 was reduced in the status epilepticus model. Dhir conducted a study to evaluate the neuroprotective role of nimesulide in a PTZ-kindled mouse model, concluding that it reduced the oxidative stress markers (malondialdehyde & nitrites) and seizure intensity [23]. Clossen and Reddy revealed the potential of cyclooxygenase-2 inhibitors after reviewing different anti-epileptic therapies, demonstrating the ability of COX-2 inhibitors to reduce the seizure frequency and cell apoptosis assessed by inflammatory & apoptotic indicators [24]. In contrast, Claycomb revealed that due to variability in response to COX-2 inhibitors, rofecoxib did not prevent the neurological damage or kindling in the PTZ-induced model, significantly [25].

Furthermore, Jiang evaluated EP2 antagonists (TG4-155 & TG6-10-1) using a pilocarpine-induced model, conducting histopathological analysis and measuring cytokines. Their findings showed reduced neurological damage and lower levels of other inflammatory markers [20]. Meanwhile, Rawat explored the therapeutic potential of TG8-260 to mitigate the chronic consequences of brain injury through biochemical assessments of oxidative stress and neuroinflammation in a post-traumatic epilepsy model. Both studies concentrated on neuroprotection, utilizing histological evaluations of neuronal damage, quantifying inflammatory cytokines, and conducting biochemical tests for apoptosis and oxidative stress. The outcomes revealed varying effectiveness depending on the model and the drug used.

This study utilized multiple techniques to evaluate the impact of cyclooxygenase-2 inhibitors on seizure outcomes in various mouse models. Polascheck assessed neuroprotection using the Racine scale and histological analysis, revealing that parecoxib reduced seizure intensity without affecting its frequency or duration in Sprague-Dawley rats [21]. L. Holtman examined rats with temporal lobe epilepsy and observed lowered PGE2 levels, while seizure incidence remained stable, employing EEG and biochemical assessments. In a follow-up study, Linda Holtman gathered EEG data to evaluate seizure frequency, identifying a significant decrease in status epilepticus duration, though mortality rates rose [22]. Akula implemented behavioral scoring and latency evaluations to measure seizure onset, showing that the seizure threshold in albino mice increased in a dose-dependent fashion, indicating greater efficacy with higher doses, while lower doses were ineffective [23].

A study with Wistar rats using the Racine scale and biochemical analysis of brain tissues for inflammatory markers showed that celecoxib reduced seizure severity and neuroinflammation [24]. One study indicated that, based on survival rates and clinical signs, Nimesulide increased seizure severity and mortality in kainic acid epilepsy models [25]. A study by Toscano, which included behavioral and histological analyses, demonstrated that long-term use of celecoxib in C57BL/6 mice worsened severity and increased sensitivity to excitotoxicity [26]. Using Swiss albino mice in a PTZ-induced epilepsy model and measuring oxidative stress markers to evaluate nimesulide's neuroprotective effects, Dhir found that it decreased kindling and oxidative stress [17]. Claycomb, through behavioral and EEG assessments, observed no significant impact of rofecoxib on seizure severity or kindling development in C57BL/6 mice [19].

Using EEG recordings and seizure length evaluations, it was concluded that an EP2 receptor antagonist reduced seizure duration in Sprague-Dawley rats in the focal injury paradigm [29]. Based on seizure surveillance and survival analysis, celecoxib decreased seizure susceptibility and enhanced survival rates in LGI1-/- mice in a genetic epilepsy model [27]. By evaluating survival rates and seizure intensity data, it was explored that both NS-398 and celecoxib aggravated seizures and increased mortality in mice with kainic acid-induced seizures [28]. Overall, these studies utilized behavioral scoring, biochemical assays, EEG monitoring, and histological investigations to assess the impact of seizures, revealing a range of results.

Histopathological analysis

The majority of histopathological research incorporated Fluoro-Jade staining for evaluating the survival of neurons and determining the extent of neural degeneration. Nissl staining was also utilized in the hippocampal region since it is selectively damaged during seizures. Celecoxib's neuroprotective effects in kainate-induced epilepsy models, noted by Jiang, were determined using comparable methodologies [13].

Multiple studies focused on the synthesis of COX-2 along with other pro-inflammatory cytokines IL-1 and TNF-α being markers of inflammation. Neuroprotection was assessed via a reduction of these inflammatory markers which portrayed how COX-2 inhibitors mitigated the inflammatory response triggered by seizure activity. To measure the oxidative stress SOD (Superoxide Dismutase), an antioxidant enzyme and a result of lipid peroxidation, malondialdehyde (MDA) was employed in some studies. Neuroprotection was described with reduced MDA and elevated SOD levels which indicated the presence of COX-2 inhibitors provided some oxidative benefits in the animal models studied. Behavioral assessments were conducted to infer neuroprotection and included rotarod for motor coordination and Morris water maze for assessment of cognitive abilities. Treated animals showed improved memory and motor function which signifies neuroprotection along with preserved neurological function.

Seizure reduction assessment methods

The Racine scale was frequently used to rate the severity of seizures based on physical features such as limb jerking and loss of posture. Multiple trials showed that Celecoxib and other COX-2 inhibitors have considerably decreased the intensity of seizures in focal epilepsy models, such as those caused by kainate and pilocarpine.

EEG has been widely utilized to measure seizure activity by detecting aberrant brain electrical patterns. Celecoxib has been shown in trials to reduce the frequency, length, and severity of seizures, especially in focal epilepsy models; effects in generalized models were less noticeable.

Longer latency periods indicate better seizure control. Several studies assessed the latency to seizure onset. Celecoxib demonstrated its effectiveness in reducing seizures by prolonging the time to seizure onset in models such as kainate- and pilocarpine-induced epilepsy.

COX-2 inhibitors have been shown to reduce seizure frequency and minimize neuronal damage in animal models of epilepsy. This effect occurs because COX-2 inhibition reduces neuroinflammation, which exacerbates neuronal stimulation and cellular damage during epileptic events. This is supported by the results from Jiang J, et al. [13], which found a significant reduction of seizures and neuroprotection from celecoxib in kainate-induced epilepsy. The current review's findings also reveal that the effectiveness of COX-2 inhibitors varies across different models of epilepsy. For instance, in animal models with focal epilepsy, such as kainate and pilocarpine-induced epileptic episodes, COX-2 inhibitors like celecoxib and rofecoxib significantly decreased seizure activity, resulting in neuroprotection. Therefore, neuroinflammation plays a central role in the pathophysiology of focal epilepsy, where cyclooxygenase-2 inhibitors have greater therapeutic potential, as described by [36].

In a generalized epilepsy model like the PTZ-induced model, the effectiveness of COX-2 inhibitors is not prominent. For example, studies 5 and 9 showed that COX-2 inhibitors had mild to moderate effectiveness in seizure reduction and neuroprotection in the PTZ-induced epilepsy model, indicating that additional neurological damage beyond neuroinflammation may limit the effectiveness of COX-2 inhibitors. These findings highlight the need for further investigation into why COX-2 inhibitors exhibit varying effectiveness in focal and generalized epilepsy models.

Another major limitation in existing studies is the lack of standardized dosing protocols. Various studies have shown better results with higher doses of COX-2 inhibitors, ranging from 10 mg/kg to 30 mg/kg. According to one of the aforementioned studies, higher doses of celecoxib, specifically 30 mg/kg, demonstrate better effectiveness in seizure reduction and neuroprotection compared to lower doses like 10-20 mg/kg. The inconsistency in results from previous studies complicates the interpretation of findings and underscores the need for further investigations to establish a standard dosing regimen applicable across different animal models of epilepsy.

Furthermore, the majority of studies focused on short-term effects, leaving behind substantial gaps in understanding long-term outcomes of COX-2 inhibitors regarding neuroprotection and seizure reduction. For investigation, whether COX-2 inhibitors can provide sustained advantages in chronic epilepsy models, long-term research is required in the future. Importance should be given to the unexplored area that long long-lasting safety of COX-2 and the chronic condition of epilepsy. Combining cyclooxygenase-2 inhibitors with other antiepileptic drugs could produce synergistic results in neuroprotection and seizure reduction by targeting neuronal excitability. This underscores the future investigation of COX-2 inhibitors along with other AEDs. To standardize treatment protocols and improve patient outcomes in terms of neuroprotection and seizure reduction, such combination therapies need to be explored [13].

This systematic review underscores the effectiveness of cyclooxygenase-2 inhibitors as a potential therapy for seizure reduction and neuroprotection. The results indicate that Cox-2 inhibitors are more effective in the focal epilepsy model as compared to the generalized epileptic model.

Despite encouraging results, the lack of an optimized dosing regimen and a small number of long-term investigations make it difficult to apply these findings in clinical practice. In the future, prospective studies should be conducted using uniform therapeutic protocols to assess the long-term safety and efficacy of COX-2 inhibitors in epilepsy patients, ideally combined with careful observations of whether different AEDs may further improve outcomes.

I would like to extend my heartfelt thanks to Dr. Muhammad Faisal Nadeem for his invaluable support in reviewing this paper and providing constructive suggestions to enhance its quality. His guidance has been crucial in shaping the direction of this study. I also take full responsibility for the content and writing of this paper, and I am proud to have independently carried out the search and analysis of the data presented herein.

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